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Research Article

Impact of waning immunity against SARS-CoV-2 severity exacerbated by vaccine hesitancy

Roles Conceptualization, Formal analysis, Investigation, Software, Writing – original draft, Writing – review & editing

Affiliations Miller Institute for Basic Research in Science, University of California, Berkeley, California, United States of America, Department of Integrative Biology, University of California, Berkeley, California, United States of America

Roles Investigation, Software, Writing – review & editing

Affiliation Department of Pathology and Cell Biology, Columbia University Medical Center, Columbia University, New York, New York, United States of America

Roles Investigation, Writing – review & editing

Affiliations Department of Integrative Biology, University of California, Berkeley, California, United States of America, Department of Biosciences, University of Exeter, Penryn, United Kingdom

Affiliation Department of Epidemiology, Brown School of Public Health, Brown University, Providence, Rhode Island, United States of America

Roles Conceptualization, Investigation, Writing – review & editing

Affiliation Network Systems Science and Advanced Computing Division, Biocomplexity Institute, University of Virginia, Charlottesville, Virginia, United States of America

Affiliation The Wellcome Trust, London, United Kingdom

Affiliations Network Systems Science and Advanced Computing Division, Biocomplexity Institute, University of Virginia, Charlottesville, Virginia, United States of America, Department of Computer Science, University of Virginia, Charlottesville, Virginia, United States of America

Affiliation Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America

Affiliation Department of Bioengineering, McGill University, Montreal, Canada

Affiliations Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America, School of Public and International Affairs, Princeton University, Princeton, New Jersey, United States of America

Roles Conceptualization, Formal analysis, Investigation, Writing – review & editing

Chadi M. Saad-Roy,
Sinead E. Morris,
Mike Boots,
Rachel E. Baker,
Bryan L. Lewis,
Jeremy Farrar,
Madhav V. Marathe,
Andrea L. Graham,
Simon A. Levin,

Published: August 5, 2024
https://doi.org/10.1371/journal.pcbi.1012211
Reader Comments

The SARS-CoV-2 pandemic has generated a considerable number of infections and associated morbidity and mortality across the world. Recovery from these infections, combined with the onset of large-scale vaccination, have led to rapidly-changing population-level immunological landscapes. In turn, these complexities have highlighted a number of important unknowns related to the breadth and strength of immunity following recovery or vaccination. Using simple mathematical models, we investigate the medium-term impacts of waning immunity against severe disease on immuno-epidemiological dynamics. We find that uncertainties in the duration of severity-blocking immunity (imparted by either infection or vaccination) can lead to a large range of medium-term population-level outcomes ( i.e . infection characteristics and immune landscapes). Furthermore, we show that epidemiological dynamics are sensitive to the strength and duration of underlying host immune responses; this implies that determining infection levels from hospitalizations requires accurate estimates of these immune parameters. More durable vaccines both reduce these uncertainties and alleviate the burden of SARS-CoV-2 in pessimistic outcomes. However, heterogeneity in vaccine uptake drastically changes immune landscapes toward larger fractions of individuals with waned severity-blocking immunity. In particular, if hesitancy is substantial, more robust vaccines have almost no effects on population-level immuno-epidemiology, even if vaccination rates are compensatorily high among vaccine-adopters. This pessimistic scenario for vaccination heterogeneity arises because those few individuals that are vaccine-adopters are so readily re-vaccinated that the duration of vaccinal immunity has no appreciable consequences on their immune status. Furthermore, we find that this effect is heightened if vaccine-hesitants have increased transmissibility ( e.g . due to riskier behavior). Overall, our results illustrate the necessity to characterize both transmission-blocking and severity-blocking immune time scales. Our findings also underline the importance of developing robust next-generation vaccines with equitable mass vaccine deployment.

Author summary

While the SARS-CoV-2 outbreak continues, the deployment of vaccines in many regions has blunted the severity of SARS-CoV-2 infections and decreased hospitalizations. However, the medium-term impacts of the duration of severity-blocking immunity, and its potential interactions with heterogeneous vaccine uptake ( e.g . from vaccine hesitancy) or more robust vaccines, remain unknown. To titrate these effects, we use immuno-epidemiological models to examine potential future scenarios. We find that sufficient vaccine hesitancy (and correspondingly higher vaccination rates among adopters) can rapidly increase the fraction of individuals infected after waned severity-blocking immunity even when robust vaccines are deployed. This result underlines that pharmaceutical developments for broadly protective vaccines should be combined with campaigns to increase vaccine uptake globally. We also show that this fraction is highly dependent on underlying immune uncertainties, which illustrates the importance of accurately measuring immune parameters for proper prediction based on hospitalization data.

Citation: Saad-Roy CM, Morris SE, Boots M, Baker RE, Lewis BL, Farrar J, et al. (2024) Impact of waning immunity against SARS-CoV-2 severity exacerbated by vaccine hesitancy. PLoS Comput Biol 20(8): e1012211. https://doi.org/10.1371/journal.pcbi.1012211

Editor: Anders Wallqvist, US Army Medical Research and Materiel Command: US Army Medical Research and Development Command, UNITED STATES OF AMERICA

Received: November 8, 2023; Accepted: May 29, 2024; Published: August 5, 2024

Copyright: © 2024 Saad-Roy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The code to reproduce the figures is available as a Supplementary Information file.

Funding: We gratefully acknowledge funding from the Miller Institute of Basic Research in Science of UC Berkeley via a Miller Research Fellowship (to C.M.S.-R.); University of Virginia Strategic Investment Fund award number SIF160, 331 (to M.V.M. and B.L.L.); National Science Foundation (NSF) Grants OAC-1916805 (CINES) (to M.V.M.), CNS-2027908 (to S.A.L) and NSF-DEB-2011109 (to M.B.); NSF Expeditions in Computing Grant CCF-1918656 (to M.V.M., B.L.L., and S.A.L.), CCF-1917819 (to M.V.M. and B.L.L.); NSF RAPID 2142997 (to M.V.M. and B.L.L.); VDH Contract UVABIO610-GY23 (to M.V.M. and B.L.L.); Centers for Disease Control and Prevention (CDC) through Pathogen Genomics356 Centers of Excellence network (PGCoE) grant 6NU50CK000555-03-01 (to M.V.M and B.L.L); the Defense Threat Reduction Agency (DTRA)357 contract HDTRA120F0017 (to M.V.M and B.L.L); the James S. McDonnell Foundation 21st Century Science Initiative Collaborative Award in Understanding Dynamic and Multi-scale Systems (to S.A.L.); the C3.ai Digital Transformation Institute and Microsoft Corporation (to S.A.L.); a gift from Google, LLC (to S.A.L.); Flu Lab (to B.T.G.); and Princeton Catalysis Initiative (to B.T.G.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a public health emergency that has had a dramatic impact across the world. In turn, it has generated a mass of epidemiological data and led to large modelling efforts [ 1 ]. Initially, guided by data analyses, a number of jurisdictions successfully implemented a range of control measures to decrease transmission, prevent a surge in infections, and decrease the burden on healthcare systems ( e.g . see [ 2 ] for a retrospective analysis). In parallel, research into pharmaceutical measures (such as vaccination or therapeutics) began, with hopes to eventually control SARS-CoV-2 transmission via vaccination. Notably, with high enough coverage, transmission-blocking vaccines ( i.e . that elicit immunity against infection) could lead to effective control and local elimination [ 3 – 6 ]. However, while the development of safe vaccines was successful ( e.g . [ 7 – 9 ]), the susceptibility of vaccinated individuals to breakthrough infection relatively soon after vaccination ( e.g . even within weeks [ 10 ]) in conjunction with the emergence of immune-escape variants ( e.g . [ 11 ]) indicates that local elimination is not possible with the current generation and partial uptake of vaccines. Since the deployment of these vaccines, many jurisdictions have changed their approach for SARS-CoV-2 management to focus on mitigation against severe infections via vaccination.

Since the onset of the pandemic, a number of important gaps in our understanding of SARS-CoV-2 epidemiology have been addressed by models [ 1 ]. For example, future transmission dynamics were illuminated in an early landmark paper by Kissler et al. [ 12 ]; the role of climate and susceptibility on pandemic dynamics was investigated by Baker et al. [ 13 , 14 ]; Lavine et al. [ 15 ] clarified the path to endemicity and the role of age structure; and others examined the role of novel variants [ 16 – 18 ]. In our previous work, we have investigated many SARS-CoV-2 immuno-epidemiological uncertainties from a qualitative perspective. First, we used and extended a simple SIR(S) model (see [ 19 ]) to show that the relative susceptibility to infection after waning of total transmission-blocking immunity ε (so that ε = 0 and ε = 1 reduce to the SIR and SIRS models, respectively, and thus ε is a proxy for the “strength of immunity”) is a key determinant of post-pandemic trajectories [ 6 ]. We then extended this framework to incorporate two-dose vaccines [ 20 ], investigate the potential effects of vaccine nationalism [ 21 ], and examine the impact of accumulating immunity on the potential future burden of chronic disease [ 22 ].

However, a number of key immuno-epidemiological questions remain. At the heart of these are uncertainties in waning immunity against severe disease ( i.e . ‘severity-blocking immunity’), and the ensuing potential outcomes in the medium term. In particular, from a public health standpoint, determining the likelihood, timing, and magnitude of the next surge in severe disease is crucial. Furthermore, many regions now rely on hospitalizations to monitor infection levels (especially with the pause of the ONS COVID-19 infection survey study in the UK); waning severity-blocking immunity could have an important effect on these dynamics, e.g . variations in the fraction of infections that require hospitalization at a given time, and thus crucially affect subsequent inferences. Additionally, since we have determined that the strength of immunity is a central parameter that shapes medium-term immuno-epidemiological dynamics [ 6 ], another outstanding unknown is the potential interplay between this parameter and the duration of severity-blocking immunity. Finally, given important developments toward mucosal vaccines [ 23 – 25 ], a major question is to determine the impacts that such vaccines with long-lasting transmission-blocking protection could have on potential outcomes and their uncertainties. For example, reducing these uncertainties may be important for robust estimates of infection levels and epidemic dynamics.

In this paper, we extend previous modelling efforts [ 6 ] to include a timescale of waning immunity against severe disease ( Fig 1A ). We begin with a characterization of the interplay between the strength of immunity, average duration of severity-blocking immunity, and vaccination rate, and their respective (and combined) impacts on infection levels in individuals with waned severity-blocking immunity. We then investigate the impact of vaccine characteristics on these dynamics, and we examine potential synoptic immuno-epidemiological landscapes. Finally, we extend our model to include heterogeneities in vaccination that are driven by unequal access or hesitancy. While we cast our results in terms of vaccine hesitancy for simplicity, our findings are broadly applicable for any setting with heterogeneous uptake in vaccination.

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( A ) Schematic of individual immunity progression after infection or vaccination. ( B ) Model flow diagram, extended from Fig 3A of [ 6 ]. Each colour denotes an infection or immunity class. ( C ) Schematic of the range of population-level outcomes based on severity-blocking immunity.

https://doi.org/10.1371/journal.pcbi.1012211.g001

Model framework

Results and discussion

Vaccination, duration of severity-blocking immunity, and dynamics of waned infections.

https://doi.org/10.1371/journal.pcbi.1012211.g002

Intuitively, as the duration of severity-blocking immunity increases, the fraction of individuals with infections after severity-blocking immunity has waned decreases (compare left to right plots of the top rows of Fig 2A–2D ). Similarly, driven by more frequent boosting of immunity, higher vaccination rates result in further decreases (compare top rows of Fig 2A–2D ). Furthermore, a lower relative susceptibility to reinfection ( i.e . stronger immunity) initially leads to a smaller fraction of infections with waned severity ( middle rows , Fig 2A–2D ). However, especially for lower vaccination rates, an increase in the strength of immunity (lower ε ) can potentially lead to larger fractions of infections that are in I w ( middle and bottom rows , Fig 2A ). Additionally, intermediate values of ε can lead to larger peaks (and deeper troughs) in I w ( top row , Fig 2A ). Interestingly, these results are partially reminiscent of the findings of [ 6 ], where, in some scenarios, stronger immunity can lead to a bigger (and delayed) second peak in infections. Finally, very high vaccination coverage ( Fig 2 ) dampens these effects because of more frequent gains in immunity.

Overall, these results illustrate an additional potential complication associated with predicting the number of total infections based on hospitalizations alone, in addition to a wide variety of known difficulties. To reduce this particular complexity, such predictions would likely necessitate robust parameter estimates for the strength of immunity and the duration of severity-blocking immunity. These could be obtained from large immuno-epidemiological cohort studies, echoing previous calls for such monitoring [ 26 – 29 ].

Future vaccine refinements

So far, we have assumed that the period of complete immunity imparted by vaccination is transient, with relatively high susceptibility after waning. While this reflects current settings with existing vaccines ( e.g . in part due to circulating immune-escape variants), pan-coronavirus and pan-sarbecovirus vaccines [ 30 ] are in development. Additionally, there have been recent landmark advances in the development of mucosal vaccines [ 23 , 24 ], which would likely be able to more successfully block transmission. Furthermore, it seems that such a mucosal vaccine could generate immunity across sarbecoviruses [ 23 ], and thus potentially generate broad immune responses to novel SARS-CoV-2 variants. In Fig 3 , we examine the impact of a more durable transmission-blocking vaccine on severity dynamics, for intermediate (1% per week) and high (2% per week) vaccination rates (panels A and B , respectively). To allow for appropriate comparisons within and across panels, we assume that the duration of vaccinal severity-blocking immunity is conserved within a column (indicated by the columnar label) within each panel. Furthermore, we assume that for 90% of that duration, vaccinal immunity also fully blocks transmission. (Note that this contrasts with Fig 2 , where the average complete vaccinal immunity was assumed to be 0.33 years.) Finally, we take a moderately optimistic assumption and assume that severity-blocking immunity after infection lasts on average 1.5 years (in Fig 2 , this value was varied concurrently with that imparted following vaccination). Finally, in each panel, the top row denotes the total infections over time, and the bottom three rows are as in those of each panel of Fig 2 .

https://doi.org/10.1371/journal.pcbi.1012211.g003

Immuno-epidemiological outlooks

So far, we have examined changes in severity dynamics via total and relative infection levels across a range of settings for the strength of immunity and durations of both severity-blocking and transmission-blocking immunity. In Fig 4 , we summarize synoptic medium-term immuno-epidemiological scenarios based on optimistic or pessimistic assumptions on severity-blocking immunity, different vaccination rates, and changes in durability of vaccines. For each scenario, we present time series of infections after severity-blocking immunity has waned and of the fraction of infections that these consist of. Below, we illustrate immunity and infection phenotypes over time. Note that at the bottom of each such area plot are the three infection types ( I P , I S , and I w ), and thus the total fraction of individuals infected is immediately seen visually. While we had previously assumed in Fig 2 (for existing vaccines) that the durations of vaccinal and natural severity-blocking immunity were equal, we now relax this assumption in optimistic scenarios for waning of severity-blocking immunity ( i.e . second column of Fig 4 ) and assume in those settings that the average duration of vaccinal severity-blocking immunity is (optimistically) slightly longer than that of natural severity-blocking immunity (2 years instead of 1.5 years). For a more durable vaccine, we assume that transmission-blocking immunity lasts on average 1.33 years, and that severity-blocking immunity lasts on average either 1.5 years (in the more pessimistic scenario with faster waning) or 3 years (if waning is optimistically slower).

https://doi.org/10.1371/journal.pcbi.1012211.g004

With a low vaccination rate, vaccinal characteristics have limited impact on immuno-epidemiological dynamics (compare left two plots and right two plots, top row , Fig 4 ). However, the relative time scale of waning severity-blocking immunity drastically alters the immune landscape ( top row , Fig 4 ). With an intermediate vaccination rate, a durable vaccine has important dynamical impacts (as also seen in [ 20 , 22 ]) ( middle row , Fig 4 ). Intermediate vaccination rates also partially modulate pessimistic outcomes if severity wanes rapidly; this is further emphasized if vaccination is increased further ( Fig 4 ). However, if severity-blocking immunity wanes rapidly and a vaccine does not provide long-lasting transmission-blocking protection, then the buildup of susceptibles with waned severity-blocking immunity remains substantial irrespective of vaccination rates (compare leftmost plots of each row, Fig 4 ). Thus, to decrease this accumulation, a high vaccination rate with a more durable vaccine is necessary.

Heterogeneities in vaccination coverage

Current vaccination rates are very variable globally and at local scales, both due to inequity in supply and hesitancy. For example, uptake of bivalent booster doses in the United States has been low, even among those who received the initial vaccines [ 31 ]. In a specific region, inequity in supply can arise from a number of issues, including due to vaccine nationalism by other regions [ 21 ], and vaccine hesitancy can emerge from underlying behavioural drivers [ 32 , 33 ]. As shown and discussed in previous work, these heterogeneities in vaccination can have important immuno-epidemiological impacts on the medium- and long-term dynamics of SARS-CoV-2 (e.g. [ 6 , 34 ]).

To investigate the potential consequences of vaccination heterogeneity on medium-term immune landscapes and burden due to infections after waning of severity-blocking immunity, we consider a simple extension of our basic framework with the addition of a group whose individuals never receive vaccinations, but otherwise mix homogeneously with individuals that are in the vaccine-adopter group (see S1 Text , electronic supplementary materials , for model equations). In Fig 5 , we illustrate the medium-term outcomes for a range of vaccine-hesitant group sizes ( rows ), for different scenarios of severity-blocking immunity and vaccine characteristics ( columns ). In all these panels, we assume that the average vaccination rate is 2% per week ( i.e . νN 1 = 0.02, where N 1 = 1 − N 2 is the fraction of individuals that are vaccine-adopters and N 2 is the fraction of individuals that are never vaccinated), which corresponds to a ‘high’ vaccination scenario in the homogeneous setting of Fig 4 .

We assume a 2% weekly vaccination rate ( c.f . bottom row , Fig 4 ), and keep the average vaccination rate constant across each row so that the vaccination rate among vaccine-adopters is ν , where νN 1 = 0.02 ( N 1 = 1 − N 2 is the fraction of vaccine adopters, and N 2 is the fraction of individuals that are vaccine-hesitant). The columnar scenarios are as in those of Fig 4 .

https://doi.org/10.1371/journal.pcbi.1012211.g005

Direct comparisons between Fig 4 ( bottom row ) and the rows of Fig 5 reveal that the homogeneous vaccination assumption is an optimistic upper bound. In particular, vaccination heterogeneity increases the fraction of infections after severity-blocking immunity has waned, and can even lead to recurrent outbreaks if there are very few individuals that are receiving vaccinations. Intuitively, these observations emerge because vaccine-adopters are a heavily vaccinated group of individuals who are re-vaccinated often. On the other hand, individuals with waned immunity that are never vaccinated can only regain immunity via infection. Thus, even in an optimistic scenario where there is slower waning of severity-blocking immunity, a large fraction of these never-vaccinated individuals have waned severity-blocking immunity. Furthermore, if there is a substantial fraction of individuals that are not receiving vaccination, a more durable vaccine has almost no immuno-epidemiological effect on the population-level dynamics (compare left two columns with right two columns, respectively, of Fig 5 , bottom row ). Finally, if the average vaccination rate decreases, the impact of the resulting vaccine heterogeneity on immuno-epidemiological outcomes is slightly attenuated ( e.g ., see S1 Fig , electronic supplementary materials where the average rate is 0.01 per week).

In Fig 6 , we examine the cumulative number of infections in I w that occur after the onset of vaccination up to year 5 (relative to population size), as a function of the fraction of individuals that are vaccine-hesitant. As in Fig 5 , we assume that the average vaccination rate is 2% per week. Across scenarios, an increase in vaccine hesitancy leads to a greater number of infections in I w . This effect is further magnified if severity-blocking immunity wanes rapidly (compare left with right panels of Fig 6 , or if vaccine-hesitants have a higher transmissibility. As illustrated in Fig 5 , vaccine hesitancy counters the deployment of a more durable vaccine ( bottom panels, Fig 6 ). In particular, sufficient vaccine hesitancy can lead to a sharp increase in the cumulative number of infections in I w ( bottom left panel, Fig 6 ). Thus, if the fraction of individuals that are vaccine-hesitant is below this threshold, there are very few infections with waned severity-blocking immunity. However, if the fraction of individuals that are vaccine-hesitant increases further beyond this threshold, the cumulative number is substantially increased. If vaccine-hesitants have a higher transmissibility, we find that this threshold occurs for a much smaller level of vaccine hesitancy ( bottom left panel , Fig 6 ), which can impact immuno-epidemiological dynamics (see S2 Fig , electronic supplementary materials for an example). Overall, these results illustrate that, even with corresponding adjustments to vaccination rates among adopters, vaccine hesitancy can substantially hinder the epidemiological benefits of more durable vaccines.

The top left , top right , bottom left , and bottom right panel depict the same scenarios as the first, second, third, and fourth columns of Figs 4 and 5 , respectively. As in Fig 5 , the average vaccination rate is constant. In each panel, the different lines denote different relative transmissibility values for vaccine hesitants.

https://doi.org/10.1371/journal.pcbi.1012211.g006

Caveats and future directions

To distill the impacts of severity-blocking immunity on potential medium-term outcomes, we have made a number of simplifying assumptions in our modelling framework that should be relaxed in future work. First, we have ignored vaccine dosing regimes (see e.g . [ 20 ]) and assumed that individuals get vaccinated at some rate, with each subsequent vaccine they obtain giving rise to similar vaccinal immunity. In reality, multiple doses can lead to more robust immunity, and incorporating explicit vaccine doses in our model could reveal subsequent impacts. Relatedly, we have ignored the potential accumulation of immunity (whether transmission-blocking or against severity) after multiple exposures. Combining this refined model with that of [ 22 ] could elucidate any intricacies that may emerge due to the interaction between accumulating immunity and waning severity-blocking immunity. We have also ignored the impact of time-dependent variable vaccination rates, and incorporating this with specific vaccination data for various regions would be valuable. Notwithstanding these complexities, we have shown that the qualitative impact of hesitancy on vaccine performance is robust to underlying assumptions. This underlines the importance of more refined and granular models for dynamics of hesitancy in future work.

While we have examined heterogeneities in vaccination, we have ignored various other heterogeneities, e.g . in transmission [ 35 , 36 ], or due to age [ 15 ] or vulnerabilities [ 37 ]. Exploring these further, and their confluence with vaccination heterogeneities and severity-blocking immunity, is an important future direction. In particular, we have assumed that interactions between individuals that are vaccine-hesitant and those that adopt vaccines are homogeneous. In reality, however, interactions within a group could be more likely than between groups. These features could enhance transmission potential and reduce the likelihood of control via vaccination (see e.g . [ 6 ] for a simple consideration of this), and examining the interplay between these effects and waning severity-blocking immunity is an important are of future research.

Relatedly, we have ignored the dynamics of human behavior [ 38 ], especially regarding adherence to nonpharmaceutical interventions ( e.g . [ 39 , 40 ]) or vaccination [ 41 , 42 ]. However, the potential feedbacks between these social and epidemiological dynamics could shape immuno-epidemiological trajectories. Thus, incorporating these features into an epidemiological-behavioral model with severity-blocking immunity would be particularly fruitful.

We have also omitted individual variations in viral loads and immune kinetics. In particular, it would be particularly insightful to formulate cross-scale models that couple our framework with within-host dynamics. Coupled with a model for viral evolution, such a framework could potentially aid in understanding viral phylodynamics of SARS-CoV-2 (see [ 29 , 43 , 44 ]). Relatedly, we have ignored the dynamics of Long COVID, and exploring the connections between this, severity-blocking immunity, and potential medium-term chronic burden is a salient avenue for future work. Overall, understanding the impacts of these various heterogeneities will require complex models with comprehensive data ( e.g . from large cohort studies [ 29 ]).

In line with previous work (see e.g . [ 6 , 20 – 22 , 45 ]) we have assumed that NPIs decrease transmission by a fixed value for fixed periods of time. However, NPIs are often implemented dynamically. Furthermore, in the absence of mandated NPIs, individuals may still choose to adhere to certain interventions ( e.g . mask-wearing, social distancing). Incorporating the underlying social dynamics that then determine NPI adherence in such a setting may be important [ 39 ]. Thus, a potentially fruitful future avenue would be to couple our simple immuno-epidemiological models with more realistic formulations of NPI adherence, calibrated to particular regions of interest.

The impacts of vaccination, transmission-blocking and severity-blocking immunity, vaccine hesitancy, varying periods of NPIs, and climatic effects on transmission can be further explored using the interactive online application at https://grenfelllab.shinyapps.io/covid19immunity/ .

As the SARS-CoV-2 outbreak continues to progress, testing and monitoring of infections has been widely relaxed and the public health emergency of international concern (PHEIC) has ended, but transmission remains high. In parallel, while the mass of data accumulated so far has improved our understanding of host immune responses following infection or vaccination, a number of uncertainties remain, especially in the duration of immunity against severe disease and in the relative susceptibility to reinfection after waning of transmission-blocking immunity.

Our simple models reveal that a large range of outcomes can emerge from uncertainties in both the duration of severity-blocking immunity and the strength of immunity, and from the confluence of these two parameters. In particular, our findings emphasize that the strength of immunity shapes immuno-epidemiological dynamics at multiple resolutions, and that the duration of severity-blocking immunity has a major effect on population-level immune landscapes and potential burdens. Thus, to properly infer infection dynamics from hospitalization data, accurate estimates of both these parameters are needed, which could be accomplished via future cohort studies monitoring immuno-epidemiology [ 29 ] and a Global Immunological Observatory [ 26 – 28 ].

Finally, we have also shown that high vaccination rates, in combination with a more durable vaccine, can alleviate pessimistic outcomes for both the buildup of susceptible individuals with waned severity-blocking immunity and for the level of infections with waned severity-blocking immunity. Our results also illustrate the importance of broad vaccination coverage, echoing previous findings that argued for equities in vaccination access [ 20 – 22 , 34 ]. In particular, we find that ignoring the specter of vaccine hesitancy in regions awash with vaccines can, at the population-level, essentially counteract important pharmaceutical developments to improve vaccine breadth and strength. Since we have shown that this result is generally robust to model assumptions on underlying uncertainties of severity-blocking immunity, our work underlines the need to identify and understand the behavioural drivers of vaccine hesitancy [ 33 ]. In tandem, since the impact of hesitancy is especially amplified if vaccine-hesitants have higher transmissibility, our results further stress the importance of nonpharmaceutical interventions in regions with elevated levels of hesitancy. Overall, to prevent pessimistic outcomes from waning severity-blocking immunity, increases in global vaccination rates in conjunction with the development of more robust vaccines are necessary.

Supporting information

S1 fig. vaccine hesitancy with a lower baseline vaccination rate..

This figure is as in Fig 5 , but with an average vaccination rate of 1% per week (instead of the 2% per week in Fig 5 ).

https://doi.org/10.1371/journal.pcbi.1012211.s001

S2 Fig. The impacts of increased transmissibility of vaccine hesitants on immuno-epidemiological dynamics.

This figure is as in Fig 5 , but with α V = 1.2.

https://doi.org/10.1371/journal.pcbi.1012211.s002

S1 Text. Supplementary information text.

https://doi.org/10.1371/journal.pcbi.1012211.s003

S1 File. Zip file with R code.

https://doi.org/10.1371/journal.pcbi.1012211.s004

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Inside eLife

Focus Issue: Call for papers in Trained Immunity

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Historically, the concept of immunological memory referred only to the ability of the adaptive immune system to develop specific responses to pathological triggers. However, this concept was challenged in 2012 by a landmark innate immune memory (also known as trained immunity) study in human and mouse experimental systems. Over the last decade, many studies built on these findings and proved that, in addition to the specific memory in adaptive immune cells, innate immune cells and structural cells can develop a non-specific memory state. Innate immune memory is a concept with evolutionary roots, as it is already present in more simple organisms such as plants, worms and insects.

The regulation of innate immune memory is based on two main pillars: metabolic reprogramming and modification of the epigenetic landscape. Numerous studies have identified triggers and regulators of trained immunity, such as certain vaccines, microbial components, metabolites, chemicals, cytokines, pathogens and diets.

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Currently, trained immunity therapeutics are being investigated in multiple settings, from organ transplant acceptance, to sepsis, cancer treatment, and atherosclerosis. However, even after one decade of research, there are still many questions to answer about the fundamental and clinical mechanisms of establishing innate immune memory, its risks, and how it can be used to improve health.

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In this eLife Focus Issue, we aim to curate Review Articles and original research articles on the history, current state, and future directions of innate immune memory studies, and overall provide a critical assessment of this new field of research. We will particularly focus on aspects that provide a better understanding of the mechanisms involving the development, regulation, maintenance and resolution of innate immune memory.

We also welcome research works on inflammatory, metabolic and epigenetic regulation of innate immune memory and its consequences in all kingdoms of life.

We hope this Focus Issue will spark new discussions and open new fields of knowledge leading to potential therapeutic interventions.

Areas of interest

We are particularly interested in research in the following areas:

Metabolic regulation of innate immune memory
Epigenetic mechanisms in innate immune memory
Inflammatory signalling in trained immunity
Targeting metabolic, epigenetic, or inflammatory signaling as therapeutic tools
Trained immunity-based vaccines
Evolutionary aspects of innate immune memory
Genetics and populational aspects in trained immunity (including gender and age)
Anti-inflammatory innate immune memory
Modulation of trained immunity responses through lifestyle and dietary interventions
Novel inducers of trained immunity
Novel cell types and non-immune primary cell models of trained immunity
Definitions of tolerance vs trained immunity vs priming
Regulatory mechanisms in trained immunity
Trained immunity in cancer
Maladaptive innate immune memory
Therapeutic applications of trained immunity-based approaches

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Researchers at Stanford Engineering have developed a nanoparticle platform that could make existing vaccines more effective, including those for influenza, COVID-19, and HIV. In addition to helping vaccine candidates produce stronger, longer-lasting immune responses, the platform will allow researchers to elicit and test different types of immune responses to determine what is most effective for protecting against specific pathogens.

“These nanoparticles elicit stronger, more robust immune responses, and the breadth of our platform allows us to readily tune the type of immune response in a way that just was not feasible with previous technologies,” said Eric Appel , an associate professor of materials science and engineering and senior author on the paper published Aug. 7 in Science Advances . “This can be a tool to understand how different types of immune responses give rise to better or worse protection – it was impossible to even ask that question before.”

A better adjuvant

Most modern vaccines teach our immune systems to recognize and fight off infections by introducing only a piece of a pathogen – such as the coronavirus’s now-infamous spike protein – instead of the whole virus. On their own, these fragments may not cause much of a reaction, so vaccines also contain adjuvants – additives that help stimulate and shape the body’s immune response. But there are currently only a handful of adjuvants available for clinical use and their effectiveness can vary widely.

“We wanted to create as potent of an adjuvant as possible,” said Ben Ou, a doctoral student in Appel’s lab and first author on the paper. “We combined two different adjuvant technologies to create a nanoparticle platform that will activate different immune pathways and improve vaccine responses.”

The researchers determined that they could attach molecules called toll-like receptor agonists, or TLR agonists, which interact with receptors on our innate immune cells, to a base nanoparticle made of saponin molecules, which have been used as effective adjuvants for decades, including in the Novavax COVID-19 vaccine. The result was an adjuvant that acted through multiple immune pathways, producing a broad, strong, long-lasting response.

Ou, Appel, and their colleagues tested their adjuvants, collectively called TLRa-SNP adjuvants, with both COVID-19 and HIV vaccine candidates. In both cases, the adjuvants greatly improved the effectiveness of the vaccines. In comparison to versions paired with an existing adjuvant, the vaccines were more potent and lasted longer. They also created immune responses that could detect and neutralize multiple versions of the pathogens – with the TLRa-SNP adjuvants, the COVID-19 vaccine candidate was effective against the original virus as well as Delta, Omicron, and other variants.

Finding the right immune response

There are multiple types of TLR agonists, each of which binds to a different immune receptor. The researchers created five different versions of their adjuvants using the saponin nanoparticle as a base platform and swapping the attached TLR agonists. While all the adjuvants were effective, each version created a slightly different type of immune response, activating different signaling proteins and prompting different actions from immune cells.

“All of our adjuvants improve overall vaccine responses, but the specific types of improvements are different,” Ou said. “If we know that a specific type of immune activation will confer better protection, we now have a platform that will allow you to pick the specific formulation that will drive that distinct response.”

With existing adjuvants, researchers can test which one creates the strongest immune response when paired with a particular vaccine, but the adjuvants are too different to allow investigations into which type of immune response would be most effective at protecting against infection for a given pathogen. The interchangeability of the TLR agonists in the TLRa-SNP adjuvants would allow researchers to tweak the nature of the immune response while maintaining the strong immune activation created by the saponin nanoparticle base.

There are other TLR agonists that could be paired with this platform, beyond the five that they tested in this paper, Ou said. He is interested in investigating others, as well as investigating the effects of using more than one type of TLR agonist at a time – the researchers have already shown that this is possible and hope to make additional bespoke nanoparticle adjuvants in the future, with the goal of developing the most effective adjuvants possible.

“This platform approach will open up opportunities for people in the field to ask more probing questions about what immunology works better in different contexts,” Appel said. “And it’s also making significantly better adjuvants.”

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For more information

Appel is a senior fellow of the Stanford Woods Institute for the Environment ; a member of Stanford Bio-X , the Stanford Cardiovascular Institute , the Wu Tsai Human Performance Alliance , the Maternal & Child Health Research Institute , the Stanford Cancer Institute , and the Wu Tsai Neurosciences Institute ; and a faculty fellow of Stanford Sarafan ChEM-H .

Additional Stanford co-authors of this research include Bali Pulendran , the Violetta L. Horton Professor in the School of Medicine; postdoctoral researcher Julie Baillet; and graduate students Maria V. Filsinger Interrante, Julia Z. Adamska, Xueting Zou, Olivia M. Saouaf, Jerry Yan, John H. Klich, Carolyn K. Jons, and Emily L. Meany.

Other co-authors on this work are from the University of Washington.

This work was funded by the Bill & Melinda Gates Foundation, the National Institute of Allergy and Infectious Disease, the Eastman Kodak Fellowship, the National Institutes of Health, the National Science Foundation, the Stanford Graduate Fellowship in Science and Engineering, and Sarafan ChEM-H.

Media contact: Jill Wu, School of Engineering: [email protected]

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Immunity boosting nutraceuticals: Current trends and challenges

Affiliation.

1 Department of Food Engineering and Technology, Institute of Chemical Technology, Mumbai, India.
PMID: 34467553
DOI: 10.1111/jfbc.13902

The immune function of the human body is highly influenced by the dietary intake of certain nutrients and bioactive compounds present in foods. The preventive effects of these bioactive ingredients against various diseases have been well investigated. Functional foods are consumed across various diverse cultures, in some form or the other, which provide benefits greater than the basic nutritional needs. Novel functional foods are being developed using novel bioactive ingredients such as probiotics, polyunsaturated fatty acids, and various phytoconstituents, which have a range of immunomodulatory properties. Apart from immunomodulation, these ingredients also affect immunity by their antioxidant, antibacterial, and antiviral properties. The global pandemic of Severe Acute Respiratory Syndrome Coronavirus-2 has forced the scientific community to race against time to find a proper and effective drug or a vaccine. In this review, various non-pharmacological interventions using nutraceuticals and functional foods have been discussed. PRACTICAL APPLICATIONS: Despite a plethora of research being undertaken to understand the immunity boosting properties of the various bioactive present in food, the findings are not translating to nutraceutical products in the market. Immunity has proved to be one of the most important factors for the health and well-being of an individual, especially when the world has been under the grip of the novel coronavirus Severe Acute Respiratory Syndrome Coronavirus-2. The anti-inflammatory properties of various nutraceuticals can come out as potential inhibitors of the various inflammatory processes such as cytokine storms, usually being observed in COVID 19. This review gives an insight into how various nutraceuticals can help in the prevention of various diseases through different mechanisms. The lack of awareness and proper clinical trials pose a challenge to the nutraceutical industry. This review will help and encourage researchers to further design and develop various functional foods, which might help in building immunity.

Keywords: PUFAs; SARS-CoV-2; antiviral; beta-glucans; immunomodulation; phytochemicals.

PubMed Disclaimer

Ingestion of beta-glucans could stimulate longer-lasting cellular immunity upon administration of COVID-19 vaccines. Kow CS, Ramachandram DS, Hasan SS. Kow CS, et al. J Food Biochem. 2021 Nov;45(11):e13959. doi: 10.1111/jfbc.13959. Epub 2021 Oct 5. J Food Biochem. 2021. PMID: 34608650 Free PMC article. No abstract available.

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Biden Misfires on Presidential Immunity

Impeachment is the Constitution’s dominant constraint on the abuse of presidential power.

Biden Misfires On Presidential Immunity

President Joe Biden muddied the constitutional waters in his recent Washington Post article. His major claim is:

This nation was founded on a simple yet profound principle: no one is above the law. Not the president of the United States. Not a justice on the Supreme Court of the United States. No one. . . . I am calling for a constitutional amendment called the No One Is Above the Law Amendment. It would make clear that there is no immunity for crimes a former president committed while in office. I share our founders’ belief that the president’s power is limited, not absolute. We are a nation of laws—not of kings or dictators.

These emphatic words were followed by Senator Majority Leader Chuck Schumer’s introduction of the “No Kings Act,” a proposal to turn Biden’s vision into law. The position of Biden and Schumer shows no appreciation of the vital role that various forms of immunity have played since the founding era. In their continuing legal efforts to discredit former president Donald Trump, they overlook the abuses that follow from excessive and multiple prosecutions of the former president—or indeed, of any public official.

American constitutional law has always included an elaborate system of implied immunities given to various kinds of officers of the United States in order to allow them to conduct their duties without fear of retribution by large numbers of aggrieved individuals. Thus in Nixon v. Fitzgerald (1982), a divided five-to-four Supreme Court, following earlier cases , held that the president was entitled to an absolute immunity in a civil suit for damages brought by a management analyst who had lost his job during a reorganization. It was well understood that the text of the Constitution said nothing about the matter, but that the president had to be given an absolute immunity, for in the absence of such immunity, “executive officials would hesitate to exercise their discretion in a way injuriously affecting the claims of particular individuals.” That peril could take place if the suit were brought while the president was still in office, or thereafter, as here, when suit was filed four years after the president left office.

The argument could not have been textual, because there was no explicit text on which the matter could turn. The only oblique reference to special protection was the Speech or Debate Clause, Art. I, Sect 6, Cl. 1, which stated that “for any Speech or Debate in either House, [Senators and Representatives] shall not be questioned in any other place.” Similar implications of absolute immunity were found in other contexts as well. Thus in Barr v. Mateo (1959), Justice John Marshall Harlan opted for an absolute privilege for any government official “within the outer perimeter of petitioner’s line of duty.” Similar absolute immunities were afforded to judges and prosecutors on the grounds that they too could not discharge their duties if subject to suit by anyone who disagreed with the outcomes they desired.

The dissent in Nixon v. Fitzgerald did not dispute that the president was entitled to some immunity, but its functional analysis insisted that the privilege should be only qualified and not absolute. Instead, it looked to Butz v. Economou (1978), which held that public officials in the Department of Agriculture charged with conducting a revenge investigation were entitled only to a qualified immunity that applied when their actions were “based on good faith and reasonable grounds.” Butz proved wholly unworkable in practice because any conscious policy decision within the executive branch could always be challenged for corrupt motive, rendering the qualified privilege a dead letter and leaving public officials subject to multiple suits both during and after their term of office. In 1988, Congress passed the so-called Westfall Act that returned to the absolute immunity of Barr v. Mateo . Qualified immunity was not mentioned in former president Trump’s immunity case.

This civil line of cases is of course distinguishable given that the Biden proposal would only strip all presidential immunity for criminal charges, a supposed self-evident truth historically never applied anywhere. The perils of this view are greater than civil suits, given that numerous cases can be brought after the president leaves office by his political nemesis—a real threat to the rule of law.

As with all cases of immunities, the ultimate question here is whether the risks of too much litigation are greater, or lesser, than those of too little. If civil litigation can dull performance in office, criminal liability can do so to a greater extent, which will make able people reluctant to take the job or to exercise vigor in pursuit of their public duty, a risk that Justice Sonia Sotomayor does not address in her impassioned dissent in Trump v. United States (2024). What makes the urge for criminal prosecution even more dangerous in this case is that it overlooks or denigrates the remedy now in place to discipline the president for abuse in office: impeachment . The current mechanism allows the Senate to impose punishment that goes no “further than [] removal from Office, and disqualification [for] hold[ing] [] any Office of honor, Trust or Profit under the United States,” which does not bar a convicted president from running for re-election. But if there is treason, bribery, or some other high crime or misdemeanor, there is no discretion—the president must be removed from office. Here is the kicker: “[B]ut the Party convicted shall nevertheless be liable and subject to Indictment, Trial, Judgment and Punishment, according to Law,” which explains what can happen afterward in an independent criminal proceeding tied to the same offense.

The impeachment power is not mentioned by Biden, but it is critical to understanding the total set of institutional arrangements. Donald Trump was impeached; his impeachment was most definitely a trial where conviction was one possible outcome. But what should be done in cases like this, where there has been an acquittal ? It is all too common to say, as Judge Tanya Chutkan did in her opinion on the subject, that an acquittal in this distinctive kind of proceeding does not bar the wide range of criminal prosecutions brought against Trump for offenses that grew out of the events of January 6. But there is absolutely no reason why the standard protections of double jeopardy, later enshrined in the Fifth Amendment to the Constitution—“nor shall any person be subject for the same offense to be twice put in jeopardy of life or limb”—should not apply to impeachment. The Constitution says nothing about what should be done in the event of an acquittal. The correct way to fill that gap is to apply the standard protection against double jeopardy. The abuse of multiple trials for the same offense is every bit as great if the first trial is in the Senate instead of in federal district court or some military tribunal.

Nor, ironically, does the Roberts opinion in Trump v. United States have anything useful to say about the subject. He does mention that after conviction, the defendant could be subject to a criminal trial, but he does not mention that this trial cannot be a free-floating affair, and must instead be tethered tightly to the grounds for the conviction. Roberts further insists that during the Pennsylvania ratification debate in 1787, James Wilson (with impeccable credentials) “similarly concluded that acquittal of impeachment charges posed no bar to subsequent prosecution.” But the exact quotation makes no reference to an acquittal but says something entirely different: “far from being above the laws, he is amenable to them in his private character as a citizen, and in his public character by impeachment .”

Pace both Biden and Roberts, one is above the laws so long as impeachment is in place. Thus, even if the convicted president remains in office, as was a distinct theoretical possibility for offenses that do not amount to treason, bribery, or a high crime and misdemeanor, he is still subject to criminal prosecution. There is no further implication that an acquittal offers no protection against open season on the president with a wide range of criminal charges, none of which can be linked to any guilty verdict, both during and after the term of office. Indeed, no one thought that after an acquittal that one, or more, criminal prosecutions could be brought for the same offense. Yet Chief Justice John Roberts never once addresses the role of an acquittal in an actual impeachment. Instead, he worries about fringe hypotheticals where somehow a president who “evades impeachment for one reason or another” or “conceals” his offense should not be allowed to escape punishment. January 6 was not such an event.

The chief justice notwithstanding, advantages of refusing to allow further punishment after an acquittal are legion. It is hard to imagine that the impeachment process (which would surely cover this case) is going to prove slower and more ham-handed than a criminal trial, which moves at glacial speed given the elaborate preliminary motions and procedural hurdles, from jury selection to admissibility of evidence, to framing of charges, to sentencing. There is, moreover, no risk of forum shopping in an impeachment trial, which must take place before the Senate with its well-established set of rules for impeachment. And the court’s troublesome line between official acts, covered by absolute immunity, and unofficial acts, which leave the president wholly exposed, does not play any role in an impeachment proceeding, where the Supreme Court does not set the rules of the game.

In dealing with matters like this, it is critical to stick to customary practices, for the political risks are too great to use half-baked legal theories to transform our legal culture. We should worry more about the degradation of the legal process.

View the discussion thread.

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Int J Environ Res Public Health

Nature Exposure and Its Effects on Immune System Functioning: A Systematic Review

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We have no archived datasets, since we did not produce any primary data in this review.

Given the drastic changes in our lifestyles and ecosystems worldwide, the potential health effects of natural environments have grown into a highly pervasive topic. Recent scientific findings suggest beneficial effects from nature exposure on human immune responses. This review aims at providing a comprehensive overview of literature published on immunomodulatory effects of nature exposure by inhalation of natural substances. A systematic database search was performed in SCOPUS and PubMed. The quality and potential bias of included studies (n = 33) were assessed by applying the EPHPP (Effective Public Health Practice Project) tool for human studies and the ARRIVE (Animal Research: Reporting of In Vivo Experiments) and SYRCLE (Systematic Review Centre for Laboratory Animal Experimentation) tools for animal studies. The synthesis of reviewed studies points to positive effects of nature exposure on immunological health parameters; such as anti-inflammatory, anti-allergic, anti-asthmatic effects or increased NK (natural killer) cell activity. Decreased expression of pro-inflammatory molecules, infiltration of leukocytes and release of cytotoxic mediators are outcomes that may serve as a baseline for further studies. However, partially weak study designs evoked uncertainties about outcome reproducibility and key questions remain open concerning effect sizes, duration of exposure and contributions of specific vegetation or ecosystem types.

1. Introduction

During the last century, environmental degradation and urbanisation have caused drastic changes in our lifestyles and living environments [ 1 , 2 ]. Today, more than half of the world’s population live in urban areas [ 3 ], and advancements of the digital era have led to a substantial rise in screen time and time spent indoors along with a decline in outdoor activities, especially in the developed world [ 4 ]. This has caused a loss of interaction between humans and nature and a progressing feeling of disconnection from the natural world, which can be defined as everything that exists independently of human conduct [ 5 ].

The estrangement from nature and other modern lifestyle changes have considerable consequences for human health [ 6 , 7 ]. However, next to being a health resource, the natural environment today also poses substantial risks to human health, not least due to air pollution and contamination of land and water caused by human activity [ 8 ]. Toxic pollution ranges among the most prominent environmental health hazards and is responsible for one out of six deaths worldwide [ 9 ]; other environmental burdens of disease include exposure to extreme heat, noise, hazardous chemicals, electromagnetic fields and natural disasters [ 8 ]. In recent years, negative health effects related to climate change have also been observed [ 10 ], especially in urban areas that are particularly at risk of developing urban heat islands (UHI) due to the lack of natural environments. The impacts of the above-mentioned environmental stressors have led to a significant rise of preventable diseases, such as non-communicable diseases (NCDs), which are today the most frequent cause of death worldwide [ 11 ]. Globally, more than 20% of all mortalities could be avoided through healthier environments and almost two-thirds of these are related to NCDs [ 12 ]. Thus, the relationships between humans, the environment and health are complex and intertwined, and exposure to intact natural environments is connected to better human health on many levels.

A growing body of evidence suggests that various forms of being exposed to nature, such as living close to, frequenting or even looking at environments dominated by living material, are able to provide salutogenic effects on human health [ 4 ]. They range from beneficial psychological to physiological outcomes such as attention restoration, improved mood, lowered anxiety and decrease in depressive symptoms, improved cardiovascular, metabolic, oncogenic, respiratory and endocrine function as well as faster healing after surgery and longer life-expectancy [ 4 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Often, these benefits are attributed to indirect effects of nature exposure, such as increased physical activity, social interactions, positive mental effects and exposure to sunlight, but recent findings have also highlighted direct physiological mechanisms that are triggered by exposure to natural environments [ 13 , 16 , 17 ]. This review focuses on direct mechanisms by which nature can affect human health, more specifically on air-borne compounds emitted by natural environments that have the potential to modulate immunological responses when inhaled, such as biogenic volatile organic compounds (BVOCs), terpenes, essential oils, charged ions, pollen, fungi and bacteria.

1.1. Nature Exposure and Immune System Functioning

A limited set of studies have pointed to potential immunological benefits from exposure to natural environments [ 16 , 21 , 22 ]. By boosting immunological defence mechanisms, natural environments might be able to positively influence immunoregulatory pathways [ 16 ]. Immunological defence mechanisms are complex, highly specified and tightly regulated processes that fight foreign pathogens by inducing phagocytosis or apoptosis, producing cytokines or antibodies and releasing inflammatory or cytotoxic mediators [ 21 , 23 ]. During a lifespan, successful immune functioning is shaped by microorganisms we encounter in our environments, from other humans and animals, and is then continuously modified by our diets or medicinal use. By being exposed to a broad variety of organisms, the immune system learns to fine-tune the balance between attack and tolerance mechanisms, and is able to develop the regulatory pathways needed to avoid overshooting immune responses to self or harmless allergens [ 24 , 25 ].

1.2. Immunoregulation through Biodiversity

Natural environments are able to provide biologically and genetically diverse microbial inputs [ 26 ]. Enhanced hygiene, smaller family sizes, increased antibiotic use and lower exposure to food bacteria in today’s industrialised parts of the world increase the likelihood of acquiring an unfavourable microbiota prone to overreact to otherwise harmless organisms [ 24 ]. There is robust evidence that a limited gut microbial diversity leads to a higher prevalence of chronic inflammatory conditions such as inflammatory bowel diseases or obesity [ 24 , 25 ], and that reduced contact with “old friends” (bacteria and parasites common in the natural environment) increases the risk of developing asthma, allergies or other hypersensitivity diseases [ 24 , 27 , 28 ].

Advancing urbanisation and fragmentation of habitats along with the increase of immunological non-communicable diseases in developed countries led to the formulation of the biodiversity hypothesis [ 29 ]. It is based on the fact that nature is one of the richest sources of microbial input, and that reduced exposure to natural environments and biodiversity may adversely affect our microbiota and its immunomodulatory capacity [ 24 ]. The biodiversity encountered in natural environments not only comprises plant, animal, microbial and fungal varieties, but also the genetic variety of those species as well as the variety of ecosystems that serve as their habitats [ 26 , 27 , 29 ]. Healthy livelihoods depend on such bio-diverse, well-functioning environments being able to provide essential ecosystem services, regulate infectious disease reservoirs and transmission and serve as pool for potential medical treatments, amongst others [ 26 ]. Thus, biodiversity loss poses an acute threat to human health.

1.3. Immunoregulation through Inhalation of Air-Borne, Volatile Substances

Next to a diverse microbial input, natural environments are also a rich source of airborne substances such as BVOCs that are emitted by above- and below-ground vegetation, rivers and oceans, soils and other natural structures [ 30 ]. BVOCs are produced by terrestrial and marine vegetation and make up approximately two thirds of total volatile organic compounds (VOCs) currently emitted in the atmosphere, with forest ecosystems considered the largest emitters of BVOCs [ 31 ]. Since their emission is temperature- and light-sensitive, the amount and type of BVOC emitted varies strongly among species, diurnal and seasonal time points and geographic and climatic regions [ 30 ]. Next to methane and dimethyl sulphide (DMS) produced by oceanic plankton, the majority of emitted BVOCs belongs to the class of terpenoids [ 30 ].

The accredited anti-inflammatory effects of terpenes include both central and peripheral mechanisms. They encompass the reduction of pro-inflammatory cytokines, modulation of oxidative stress and inhibition of tissue infiltration by inflammatory cells, thereby being able to reduce both acute and chronic inflammatory responses in diverse pathological settings [ 32 , 33 ]. Moreover, terpenes can also exert immune-stimulatory effects such as increasing phagocytic activity, enhancing innate immune responses, repressing the expression of certain pro-inflammatory cytokines and increasing immunoglobulin levels [ 21 ]. The anti-tumour effects observed are mainly associated with inducing tumour cell apoptosis, inhibiting their proliferation and preventing metastasis [ 33 ]. Many of these effects are mediated by essential immunological cellular components, such as natural killer (NK) cells [ 33 ].

Besides terpenes, charged ions that occur in the air close to waterbodies might also have beneficial effects on immune functioning, especially in the respiratory tract [ 34 , 35 ]. Water spray is also a source of microbial input [ 24 ], and the inhalation of charged ions, airborne microbes and phytoncides emitted by trees is known to affect systemic immune responses in various ways [ 20 ].

By removing airborne pollutants, forest ecosystems are also responsible for health benefits resulting from improved air quality. Air pollution is estimated to cause 6.5 million annual premature deaths worldwide already today [ 9 ]. Dry deposition of particulate matter (PM) and absorption of gaseous pollutants by leaf stomata is able to remove up to 4 tons of airborne pollution per square mile and year [ 36 ]. This impacts acute and chronic immunological mechanisms by protecting against the development of respiratory diseases and significantly lowers mortality rates in the local population [ 37 ]. However, trees can also adversely affect air pollution. BVOCs are highly reactive molecules and can form secondary organic aerosols (SOA) with anthropogenic VOCs, thereby producing ozone [ 30 ]. SOAs directly affect the climate by scattering incoming solar radiation and acting as cloud condensation nuclei, thereby significantly changing the planet’s radiative balance and potentially leading to a net cooling effect by increasing cloud albedo [ 30 , 38 ]. This increased cloud cover may locally trap pollutants and lead to adverse health effects [ 15 ].

Thus, natural environments do not exclusively have beneficial effects on the immune system, but can sometimes even pose a threat to proper immune functioning. A wide range of microorganisms such as pollen grains, fungal spores, mycelium, algae and bacteria are produced by vegetation, especially grasses, and act as potential allergens and might therefore be harmful by causing or exacerbating allergic reactions [ 20 , 36 ]. A growing number of studies have tried to assess the effects of nature exposure on asthma and allergies; however, the overall outcome of these studies is inconsistent and ranges from positive and negative to no associations [ 13 ].

1.4. Health-Promoting Ecosystem Services and Their Effects on the Immune System

In order to understand the relationship between nature and immunological health in detail and to provide a thorough analysis of its long- and short-term co-benefits and potential adverse effects, it is important to consider the services that ecosystems provide either directly or indirectly for humans to sustain their lives and enhance their wellbeing. Many of these ecosystem services are health-supporting; they provide biodiversity and reduce harmful exposures, e.g. to extreme heat or air and water pollution [ 36 ]. The multitude and diversity of human health benefits observed from nature suggest a plurality of mechanisms that either stand side by side or interact in one broad pathway of action [ 16 ]. The immune system is a key player in maintaining physiological homeostasis and in sustaining health over disease in the human body. Current literature suggests that enhanced immune functioning can be the outcome of a vast majority of observed nature-related health effects [ 16 ]. It has therefore been postulated as a promising candidate that may incorporate many different health effects into one central pathway.

The aim of this review is to provide a comprehensive overview of literature published on the immunomodulatory effects on human health following exposure to natural environments. What distinguishes the paper at hand is its focus on inhalation as the only way of taking in the biogenic substances analysed. The goal was to define a baseline of reliable data that can be used as a starting point for future in-depth immunological research, to shed light on consistencies and potential discrepancies and to elucidate knowledge gaps in this field.

In order to establish a holistic perspective and stimulate a broad interdisciplinary research agenda on immunoregulation through nature exposure, different experimental setups were included in this review. Animal experiments represent an important data source that helps create both initial hypotheses as well as elucidate causal pathways through which nature unfolds its various health benefits. Therefore, both human as well as animal experimental studies were evaluated and rated for their scientific quality.

2. Methodology

The methodological approach for the present review followed the guidelines provided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [ 39 ].

2.1. Search Strategy

A structured literature search was carried out in the databases Scopus and PubMed between February and March 2020 and included all articles published up to the search date. The search string was designed to combine different nature-based interventions with different immune-related physiological outcomes (using the Boolean operators AND and OR). A search for article titles including the following keywords was performed:

Nature OR “natural environment” OR forest* OR ecosystem* OR vegetation OR “green infrastructure” OR wood* OR greenness OR greenspace OR outdoor OR biodiversity OR shinrin yoku OR BVOC OR “biogenic volatile organic compound” OR “natural volatile organic compound” OR phytohormon* OR phytoncide* OR “plant gas” OR “essential oil” OR fragrance OR aromatherapy

immun* OR inflamma* OR antiinflamma* OR interleukin* OR cytokin* OR allergen* OR asthma* OR physiologic* OR “NK cell” OR “natural killer“.

When possible, the search was limited to articles and conference papers, and excluded other document types.

The field of immunological health provisioning through nature exposure is multidisciplinary and entails studies with very different methodological approaches which yet have no common narrative, let alone keywords, methodological guidelines or shared objectives. This made it challenging to formulate a fitting keyword search that incorporated all possible wordings and headline formulations into one comprehensive search string and selectively targeted relevant studies in the wide-spanning field. Therefore, we included snowballing as additional search strategy by screening related reviews as well as references of the selected studies, which considerably expanded the results found (see limitations).

2.2. Study Selection

Articles retrieved from the database search were roughly screened according to title and abstract for meeting the eligibility criteria, which were defined as follows:

Analysed species were limited to mammals, and ranged from humans (no age or health status restrictions) to animal studies. In vitro studies on cell lines or primary cell material were excluded. A wide range of different nature exposures was considered in the inclusion criteria, such as all kinds of outdoor nature (urban nature, wilderness, green and blue spaces…), particles and gases released or produced by nature (BVOCs, pollen, fungi, moulds…) or man-made nature products (essential oils, fragrances, aromas, wood panels…). Excluded were foods, roots, traditional medicine, drugs and venoms. Only studies with no or light activities were included, since physical exercise is known to have immunological effects in itself [ 15 , 16 ]. Concerning the route of administration, only inhalation or olfactory stimulations were included. This likewise entailed being intentionally exposed to volatile substances in an experimental setting as well as normal breathing of ambient air while being exposed to natural environments, such as forest bathing or “Shinrin Yoku” (Japanese term for “taking in the forest atmosphere” [ 33 , 40 ]). Furthermore included were exposures to specific housing conditions or residential and recreational stays in nature. All other kinds of exposure (like simply viewing nature from inside) or administration routes (such as oral, topic or parenteral) were beyond the scope of this review and therefore not considered. Furthermore excluded were exposures specific to a certain situation or professional context, such as occupational wood dust exposure of forest workers or wood smoke from forest fires or stoves. Studies involving viral diseases and parasite infestations (e.g., Lyme disease, boreliose infections) were also not part of this review.

To be eligible, studies had to examine physiologic parameters attributable to immune system responses like cellular properties, cytokine and antibody levels, or disease-related outcomes serving as indicators for an immune response, e.g. respiratory symptoms, autoimmune conditions or allergic sensitisations. Due to limited resources, the language of included articles was limited to English and the study type to peer-reviewed intervention studies. None of the investigators were contacted, and no unpublished data was retrieved.

2.3. Quality Assessment

The included set of articles was divided into human and animal studies, and three distinct but specific quality assessment tools were applied. Each study was independently evaluated by two researchers. In case of disagreements, the individual assessments were discussed and a consensus was found between the researchers.

For human studies, the risk of bias was evaluated following the quality assessment tool developed by the Effective Public Health Practice Project (EPHPP) [ 41 ]. Based on six parameters (selection bias, study design, confounders, blinding, data collection methods and withdrawals/dropouts), the studies were rated and classified into overall strong (1), moderate (2) or weak (3). Scoring criteria followed the publicly available EPHPP dictionary. Two or more weak parameters classified a study as overall weakly designed. An overall moderate study may only be rated weak in one parameter, while an overall strong study required no weak parameters.

The quality assessment of animal studies was carried out according to the “Animals in Research: Reporting In Vivo Experiments” (ARRIVE) guidelines for good reporting practice in animal research [ 42 ]. These guidelines provide 20 questions concerning the quality of design and reporting in animal research and give a useful indication of the adoption of good scientific practise in animal studies. We rated each question with points from 1 (good/reported) to 3 (weak/not reported).

Additionally, we evaluated the risk of bias of each animal study based on the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool [ 43 ], which was adapted from the Cochrane Collaboration’s Risk of Bias (RoB) tool and developed specifically for the qualitative rating and systematic comparison of experimental animal studies. The SYRCLE tool addresses 10 different domains which are categorised into assessment of selection bias, performance bias, detection bias, attrition bias, reporting bias and other biases. By rating the potential biases of each individual study, we assessed the study to have a low, high or unclear risk of bias.

3.1. Article Selection

The initial database search returned 5167 records (3278 from Scopus and 1889 from PubMed). After a first screening of titles and abstracts and removal of duplicates, 65 studies remained for full-text analysis. Full-text reading resulted in a total of 13 studies that met all inclusion and exclusion criteria. Additional articles were identified through a snowballing search based on scanning references and reviews; 20 of those met the eligibility criteria and were therefore included in the final selection. Summing up, a total of 33 articles were included in this systematic review, comprising both human (n = 20) and animal (n = 13) intervention studies. Figure 1 illustrates the respective stages in the study selection process.

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Flowchart of study selection process (following PRISMA guidelines).

3.2. Characteristics of Included Studies

An overview of included human and animal studies is given in Table 1 and Table 2 and shows the year of publication, country of study origin, study design, sample size, sample characteristics, age and sex of sample, type of intervention and control and duration of intervention.

Characteristics of included human studies.

Main Author	Year	Country	Study Design	Sample Size (Intervention/Control)	Sample Characteristics	Sample Age	Sample Sex	Intervention	Control	Duration

Han et al. [ ]	2016	South Korea	Pre-post (2 groups) CCT	61 (33/28)	Adults with chronic pain	25–49	Mixed	Forest bathing (pine, oak maple forest)	Normal daily routine	2 days
Im et al. [ ]	2016	South Korea	Pre-post (2 groups crossover) RCT	41	Healthy students	18–35	Mixed	Forest environment (pine tree forest)	Urban environment	2 h
Jia et al. [ ]	2016	China	Pre-post (2 groups) CCT	18 (10/8)	COPD patients	61–79	Mixed	Forest bathing	Urban stay	3 days
Kim et al. [ ]	2015	South Korea	Pre-post (1 group)	11	Adults with breast cancer	25–60	Female	Forest therapy	/	14 days
Li et al. [ ]	2007	Japan	Pre-post (1 group)	12	Healthy adults (office workers)	37–55	Male	Forest bathing	/	3 days (2–4 h/day)
Li et al. [ ]	2008a	Japan	Pre-post (1 group)	13	Healthy adults (nurses)	25–43	Female	Forest bathing	/	3 days (2–4 h/day)
Li et al. [ ]	2008b	Japan	Pre-post (1 group crossover)	12	Healthy adults	35–56	Male	Forest bathing	Urban stay	3 days (2–4 h/day)
Lyu et al. [ ]	2019	China	Pre-post (2 groups) CCT	60 (45/15)	Healthy adults	19–24	Male	Forest bathing (bamboo forest)	Urban stay	3 days
Mao et al. [ ]	2012a	China	Pre-post (2 groups) CCT	20 (10/10)	Healthy students	20–21	Male	Forest bathing (broad-leaved forest)	Urban stay	2 days
Mao et al. [ ]	2012b	China	Pre-post (2 groups) CCT	24 (12/12)	Elderly patients with hypertension	60–75	Mixed	Forest bathing (broad-leaved forest)	Urban stay	7 days
Mao et al. [ ]	2017	China	Pre-post (2 groups) CCT	33 (23/10)	Elderly patients with chronic heart failure	66–79	Mixed	Forest bathing (broad-leaved forest)	Urban stay	4 days
Mao et al. [ ]	2018	China	Pre-post (2 groups) CCT	20 (10/10)	Elderly patients with chronic heart failure	66–79	Mixed	Second forest bathing trip (broad-leaved forest) after 4 weeks break	Urban stay after previous forest bathing trip 4 weeks ago	4 days
Seo et al. [ ]	2015	South Korea	Pre-post (1 group)	21	Children with asthma	7–12	Mixed	Forest bathing (fir tree forest)	/	4 days
Seo et al. [ ]	2015	South Korea	Pre-post (1 group)	27	Children with atopic dermatitis	7–12	Mixed	Forest bathing (fir tree forest)	/	4 days
Tsao et al. [ ]	2018	Taiwan	Retrospective study (pre-post 2 groups)	200 (90/110)	Healthy adults	34–56	Mixed	Forest workers	Urban residents	1 year
Tsao et al. [ ]	2018	Taiwan	Pre-post (1 group)	11	Healthy adults	/	/	Forest bathing (coniferous forest)	/	5 days

Li et al. [ ]	2009	Japan	Pre-post (1 group)	12	Healthy adults	37–60	Male	Inhalation of phytoncides (vaporized hinoki cypress stem oil) in urban hotel room	/	3 days

Kiecolt-Glaser et al. [ ]	2008	Ohio, USA	Pre-post (1 group crossover)	56	Healthy adults	18–43	Mixed	Inhalation of fragrances (lavender, lemon)	Inhalation of water vapour	1.25 h
Komori et al. [ ]	1995	Japan	Pre-post (2 groups)	20 (12/8)	Adults with depression	26–53	Male	Inhalation of citrus fragrance mix (limonene, citral, other EOs)		4–11 weeks
Trellakis et al. [ ]	2012	Germany	Pre-post (1 group crossover)	32	Healthy adults	20–45	Mixed	Inhalation of stimulant fragrances (grapefruit, fennel, pepper)	No fragrance exposure	3 days (30 min/day)
Trellakis et al. [ ]	2012	Germany	Pre-post (1 group crossover)	32	Healthy adults	20–45	Mixed	Inhalation of relaxant fragrances (lavender, patchouli, rose)	No fragrance exposure	3 days (30 min/day)

Gaisberger et al. [ ]	2012	Austria	Pre-post (2 groups) CCT	54 (27/27)	Children with allergic asthma	8–15	Mixed	Waterfall exposure (WF+) in national park	No waterfall exposure (WF-) in national park	3 weeks (1 h/day)
Grafetstätter et al. [ ]	2017	Austria	Pre-post (3 groups) CCT	91 (33/32/26)	Adults with stress (Pre-treated with oral cholera vaccination)	19–61	Mixed	Hiking in national park with waterfall exposure (WF+)	Hiking in national park without waterfall exposure (WF-)	1 week (1 h/day)

Characteristics of included animal studies.

Main Author	Year	Country	Study Design	Sample Size (Number per Group)	Sample Characteristics	Sample Age	Sample Sex	Intervention	Control	Duration

Ahn et al. [ ]	2018a	South Korea	Animal	35 (7)	Mice Pre-treated with LPS	7 weeks	Male	Housing with BVOC wood panels (C. obtusa, P. densiflora) LPS	Housing without wood panels LPS	4 weeks
Ahn et al. [ ]	2018b	South Korea	Animal	49 (7)	Mice Pre-treated with OVA	5 weeks	/	Housing with BVOC wood panels (C. obtusa, P. densiflora, P. koraiensis, L.kaempferi) OVA	Housing without wood panels OVA	27 days
Yang et al. [ ]	2015	South Korea	Animal	/	Mice Dinitrochlorbenzene (DNCB)-induced atopic dermatitis (AD)-like disease model	7 weeks	/	Exposure to BVOC (C. obtusa)	Exposure to vehicle	8 weeks

Bastos et al. [ ]	2011	Brazil	Animal	ca. 35 (7–10)	Guineau pigs Pre-treated with OVA	/	Male	Eucalyptol (1,8-cineol) inhalation OVA	Saline inhalation OVA	15 min
Kennedy-Feitosa et al. [ ]	2019	Brazil	Animal	40 (10)	Mice Pre-exposed to cigarette smoke (CS)		Male	Eucalyptol (1,8-cineol) inhalation CS	Vehicle inhalation CS	120 days (15 min/day)
Lee et al. [ ]	2016	South Korea	Animal	/	Mice Pre-sensitised to Der p (house dust mite allergen; HDM)	6 weeks	Female	Eucalyptol (1,8-cineol) inhalation Der p	Vehicle inhalation Der p	/

Bibi et al. [ ]	2015	Israel	Animal	30 (10)	Mice Pre-treated with OVA	8 weeks	Female	Housing with Limonene-treated wood bedding OVA	Housing with untreated wood bedding OVA	30 days
Hirota et al. [ ]	2012	Japan	Animal	30 (10)	Mice Pre-sensitised to Der f (house dust mite allergen; HDM)	6 weeks	Male	Limonene inhalation Der f	No inhalation Der f	31 days
Keinan et al. [ ]	2005	Israel	Animal	40 (10)	Rats Pre-treated with OVA	4 weeks	/	Limonene inhalation (ozone scavenger) Eucalyptol inhalation (inert to ozone) OVA	No inhalation OVA	1 week

Hansen et al. [ ]	2013	Denmark	Animal	ca. 40 (9–10)	Mice Pre-treated with OVA	5-6 weeks	Female	Limonene inhalation Limonene + ozone inhalation OVA	No inhalation Ozone inhalation OVA	14 weeks
Hansen et al. [ ]	2016	Denmark	Animal	40 (10)	Mice Pre-treated with OVA	6 weeks	Female	Limonene inhalation	Air inhalation	3 days (60 min/day)

Naka-mura et al. [ ]	2009	Japan	Animal	12 (4)	Rats Stressed by restraining in tube	7–8 weeks	Male	Linalool inhalation Stress	No inhalation Stress	2 h

Fujiwara et al. [ ]	1998	Japan	Animal	84 (12)	Mice Stressed with high pressure	8–10 weeks	Male	Fragrance exposure (lemon, oak moss, labdanum, tuberose) Stress	No fragrance exposure Stress	24 h

3.2.1. Characteristics of Human Studies

Among the included human studies, only one study was designed as a randomised controlled trial (RCT) [ 44 ] and nine studies were controlled clinical trials (CCT) [ 34 , 35 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. The rest were designed as one group pre-post intervention studies [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ], three of which were carried out as one group crossover studies [ 55 , 59 , 61 ]. Sample sizes ranged between 11 and 200 subjects, most studies investigating 10–20 individuals per group. Participant characteristics ranged from healthy individuals to individuals suffering from diverse chronic conditions, and comprised children, adults and elderly people from both genders aged seven to 79 years. The types of interventions could roughly be divided into three experimental setups: forest bathing, experimental inhalation of BVOCs or fragrances and exposure to waterfalls. Forest bathing interventions and waterfall exposures were examined in 14 [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 52 , 53 , 54 , 55 , 56 , 57 ] and two [ 34 , 35 ] studies, respectively. Four studies analysed the effects of BVOC [ 58 ] or fragrance [ 59 , 60 , 61 ] inhalation on human subjects ( Table 1 ).

3.2.2. Characteristics of Animal Studies

The majority of included animal studies were carried out in mice [ 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ] (10 out of 13), while two studies used rats [ 72 , 73 ] and one study worked with guinea pigs [ 74 ]. All studies used a pre-treatment such as lipopolysaccharide (LPS), ovalbumin (OVA), Der p ( Dermatophagoides pteronyssinus), Der f ( Dermatophagoides farina) or other to experimentally induce an immune reaction which served as control condition for the actual intervention. Sample sizes ranged between 12 and 84 animals; most studies analysed 10 animals per group. Animals were between four and 10 weeks of age and comprised both genders. The types of interventions could be divided into the following experimental setups: inhalation of BVOCs [ 62 , 63 , 64 ], eucalyptol [ 65 , 66 , 74 ], limonene [ 67 , 68 , 73 ], mix of limonene/ozone [ 69 , 70 ], linalool [ 72 ] and other fragrances (lemon, oak moss, labdanum and tuberose) [ 71 ]. Three studies evaluated the effects of different housing conditions in laboratory animal cages equipped with different wood beddings [ 62 , 63 , 67 ] ( Table 2 ).

3.3. Quality Assessment

3.3.1. quality assessment of human studies.

For methodological quality assessment, we subjected all included human studies to a risk of bias assessment following the EPHPP quality assessment tool [ 41 ].

According to the EPHPP tool, one study was rated overall strong [ 61 ], four studies as overall moderate [ 48 , 49 , 52 , 56 ] and 15 studies got a weak overall score [ 34 , 35 , 44 , 45 , 46 , 47 , 50 , 51 , 52 , 53 , 54 , 55 , 57 , 58 , 59 , 60 ] ( Table 3 ). The weak ratings were mainly due to lack of information on recruitment procedures, the use of self-referred or non-representative samples (selection bias) and missing information on blinding. Blinding was neither described for study assessors nor for participating subjects, the latter being hardly applicable in multi-day forest bathing studies where the exposure to environmental surroundings is obvious. In order to more representatively evaluate the methodological quality of included studies, we therefore chose to also provide an alternative overall score excluding the “blinding” parameter. This resulted in five studies being rated as overall strong, nine as moderate and six as weak ( Table 3 , last column). More information on scoring criteria is given in the Supplementary Material .

Quality assessment of human intervention studies following the EPHPP tool.

								Overall Score
		Selection Bias	Study Design	Con-founders	Blinding	Data Collection	Dropouts
Gaisberger et al.	2012	2	1	1	3	1	3	3	2
Grafetstätter et al.	2017	3	1	2	3	1	3	3	3
Han et al.	2016	2	1	1	3	1	3	3	2
Im et al.	2016	2	1	1	3	1	3	3	2
Jia et al.	2016	3	1	1	3	1	3	3	3
Kiecolt-Glaser et al.	2008	2	2	3	1	3	1	3	3
Kim et al.	2015	2	2	NA	3	1	1	2	1
Komori et al.	1995	3	2	2	3	1	3	3	3
Li et al.	2007	3	2	NA	3	1	2	3	2
Li et al.	2008a	3	2	NA	3	1	3	3	3
Li et al.	2008b	3	2	NA	3	1	2	3	2
Li et al.	2009	3	2	NA	3	1	2	3	2
Lyu et al.	2019	3	1	2	3	1	2	3	2
Mao et al.	2012a	3	1	1	3	1	2	3	2
Mao et al.	2012b	3	1	1	3	1	2	3	2
Mao et al.	2017	2	1	1	3	1	1	2	1
Mao et al.	2018	2	1	1	3	1	1	2	1
Seo et al.	2015	2	2	NA	3	1	2	2	1
Trellakis et al.	2012	2	2	NA	2	1	1	1	1
Tsao et al.	2018	3	2	1	3	1	3	3	3

1 = strong (green), 2 = moderate (yellow), 3 = weak (red), NA = not applicable (one-group studies). An alternative overall score excludes the “blinding” category (*).

3.3.2. Quality Assessment of Animal Studies

All animal studies were evaluated following two standardised quality assessment guidelines: ARRIVE assessment tool [ 42 ] and SYRCLE’s risk of bias tool for animal studies [ 43 ]. The results from the ARRIVE assessment, entailing 20 categories, are summarised in Table 4 . Specific information on assessment criteria for individual ratings are provided in the Supplementary Material .

Quality assessment of animal intervention studies following the ARRIVE guidelines.

(a)
		1	2	3	4	5	6	7	8	9	10
		Title	Abstract	Introduction		Methods

Ahn et al.	2018a	2	1	1	1	1	3	1	1	1	2
Ahn et al.	2018b	2	1	1	1	2	2	1	2	1	2
Bastos et al.	2011	1	1	1	1	1	2	1	2	3	3
Bibi et al.	2015	1	2	1	1	2	2	1	2	1	2
Fujiwara et al.	1998	1	1	2	2	3	2	2	2	2	1
Hansen et al.	2013	2	1	1	2	1	2	1	1	1	2
Hansen et al.	2016	1	1	1	1	1	1	1	1	1	2
Hirota et al.	2012	1	2	2	3	2	1	1	1	1	2
Keinan et al.	2005	1	1	1	1	2	3	1	3	3	3
Kennedy-Feitosa et al.	2019	1	1	2	2	2	2	1	1	1	2
Lee et al.	2016	2	1	1	1	2	3	1	1	3	3
Nakamura et al.	2009	2	2	2	3	3	2	1	2	1	2
Yang et al.	2015	1	1	1	1	1	3	3	2	1	3




Ahn et al.	2018a	3	1	1	3	3	2	3	2	2	1
Ahn et al.	2018b	3	1	1	3	3	2	3	2	2	3
Bastos et al.	2011	3	1	1	3	3	2	3	2	2	2
Bibi et al.	2015	3	1	1	3	1	2	3	2	1	1
Fujiwara et al.	1998	3	3	2	3	3	2	3	2	2	3
Hansen et al.	2013	3	1	1	1	2	1	3	1	1	1
Hansen et al.	2016	2	1	1	1	1	2	3	1	1	1
Hirota et al.	2012	2	1	1	3	1	2	3	2	2	2
Keinan et al.	2005	3	2	2	3	3	2	3	3	2	3
Kennedy-Feitosa et al.	2019	3	1	1	3	1	2	3	1	1	1
Lee et al.	2016	3	1	1	3	3	2	3	2	2	1
Nakamura et al.	2009	3	1	1	3	1	2	3	2	2	3
Yang et al.	2015	3	1	1	3	3	2	3	2	2	1

1 = reported/strong (green), 2 = moderate (yellow), 3 = not reported/weak (red).

Most studies provided a good to moderate title, abstract and introduction section. In the methods section, most studies met the criteria concerning the description of experimental procedures, animal details and housing and husbandry conditions (categories 7–9), while no study appropriately provided a calculation of sample sizes (category 10) or described the method of allocation to experimental groups (category 11). Almost all studies provided sufficient information regarding the experimental outcomes (category 12) and included a description of the statistical analysis of the results (category 13).

In the results section, we detected more reporting shortcomings than in the other categories. A failure in reporting group-specific baseline data of experimental animal characteristics (category 14) as well as reporting adverse events (category 17) was asserted in almost all studies. The majority of studies failed to monitor and report specific baseline characteristics such as body weight. Moreover, many studies did not report any information on the numbers of animals included in the final analysis (category 15), nor refer to drop out rates or reasons for exclusions. All studies included a measure of precision (e.g. bars representing standard deviations) in their outcome report (category 16), but only one study [ 69 ] also provided data on the number of individual data points within one group, which should be considered the gold standard of outcome reporting.

Regarding the discussion section, most studies interpreted the implications of their findings within the current scientific literature; however many failed to elaborate on study limitations (category 18) and generalisability of study outcomes (category 19), i.e. translation of outcomes into the human system.

A risk of bias assessment following the SYRCLE’s risk of bias (RoB) tool for animal studies [ 43 ] was conducted to complement the ARRIVE quality assessment. According to the SYRCLE RoB tool, many studies did not adequately report measures taken to reduce potential risk of biases in several categories. Randomisation and blinding of the experimental setup were rarely reported, and no study had performed a preceding calculation of sample sizes. All results of the SYRCLE risk of bias assessment are provided in the Supplementary Material (Table S1) .

3.4. Outcomes and Synthesis

3.4.1. outcomes of human studies.

The majority of studies measured either anti-inflammatory or cytotoxic effects following nature exposure. Experimental parameters analysed were mainly expression of pro- or anti-inflammatory cytokines (mostly IL-6 and TNFα) in serum, numbers and percentages of immune cell subsets (mostly NK cells and T cells) and expression of cytotoxic mediators (perforin, granzyme A/B and granulysin) as well as cytotoxic NK cell activity. Some studies examined several outcomes. Overall, a positive effect was observed on most immunological parameters measured; four studies showed no significant changes. An overview of outcomes measured in studies with human subjects is presented in Figure 2 .

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Overview of outcomes from human studies.

Most studies with human subjects examined the effects of forest bathing trips of varying lengths on different immunological parameters. Seven (out of 14) forest bathing studies analysed inflammatory cytokine expression and unanimously reported either a decrease in pro-inflammatory and/or an increase in anti-inflammatory cytokine levels [ 44 , 46 , 48 , 49 , 50 , 51 , 56 ], implicating anti-allergic or anti-asthmatic outcomes from being exposed to forest environments. One of the studies also evaluated changes in clinical scores of patients with asthma and atopic dermatitis after a forest trip and concluded a relief of clinical symptoms and beneficial effects of forest bathing on spirometric outcomes [ 56 ].

Ten (out of 14) forest bathing studies elucidated the effects on the distribution of immune cell subsets as well as on their distinct effector activities, with a special focus on NK cells. The majority of these studies (8 out of 10) reported an increase either in NK cell number or in NK cell activity [ 45 , 47 , 52 , 53 , 54 , 55 , 57 ], which was measured either directly by flow cytometry or indirectly by assessing the level of cytotoxic mediators circulating in the blood. Two forest bathing studies did not observe any significant changes in NK cell outcomes [ 46 , 50 ]. One additional study reported an increase in NK cell number and activity after the isolated inhalation of phytoncides under laboratory conditions [ 58 ], concluding that volatile substances released by plants are responsible for the effects observed in natural environments.

Three studies examined the outcomes of inhaling different fragrances (citrus mix, lavender, lemon, grapefruit, fennel, pepper, patchouli and rose) on immunological parameters such as cytokine and chemokine levels, cell ratios and strength of immune response to infection. Two of these studies reported no significant effect of fragrance exposure on levels of circulating cytokines and chemokines [ 59 , 61 ], while one of them observed a lower hypersensitivity to candida infection compared to control [ 59 ]. Another study reported beneficial effects on immune cell ratios after fragrance exposure [ 60 ].

Two studies looked at potential health effects of charged ions in ambient air in the vicinity of waterfalls. One of them detected significantly decreased pro-inflammatory cytokine levels combined with enhanced lung function and reduced clinical symptoms in children with allergic asthma, which was suggested to be due to an induction of circulating regulatory T cells [ 35 ]. The other study reported that exposure to waterfalls led to an activated immune system and also improved lung function [ 34 ].

Table 5 provides a comprehensive summary of all outcomes from human studies.

Outcomes of human studies. Significances are given with p < 0.05, p < 0.01 and p < 0.001; NS = not significant, NA = not applicable. A non-significant trend is described as “Decrease/Increase, NS”. If significances are not given, it is described as “Decrease/Increase, NA”.

				Outcome
Main Author	Year	Title	Measure	Intervention (Compared to Baseline)	-Value	Control (Compared to Baseline)	-Value	Comparison (Intervention Compared to Control)	-Value	Conclusion	Comment

Han et al. [ ]	2016	The effects of forest therapy on coping with chronic widespread pain	NK cell activity	Increase	0.001	NS		Increase	NA	NK cell activity increases after a forest bathing trip in adults with chronic pain.
Im et al. [ ]	2016	Comparison of effect of two-hour exposure to forest and urban environments on cytokine, anti-oxidant and stress levels in young adults	IL-6 level in serum					NS		Pro-inflammatory cytokine level (IL-8 and TNFα, but not IL-6) is reduced in healthy students after a forest bathing trip.
			IL-8 level in serum					Decrease	0.001
			TNFα level in serum					Decrease	0.001
			Glutathione peroxidase (GPx) level in serum					Increase	0.05
Jia et al. [ ]	2016	Health effects of forest bathing trip on elderly patients with chronic obstructive pulmonary disease	CD8+ T cell number and %	NS		NS		NS		Forest bathing reduces pro-inflammatory cytokine levels, but not proportions of CD8+ T, NK or NKT cells or GrB expression in COPD patients.
			NK cell number and % (CD3-CD56+)	NS		NS		NS
			NKT cell number and % (CD3+CD56+)	NS		NS		NS
			Perforin expression in CD8+ T cells (flow cytometry)	Decrease	0.001	Decrease	NA	Decrease	0.01
			Perforin expression in NK cells (flow cytometry)	Decrease	0.001	Decrease	NA	NS
			Perforin expression in NKT cells (flow cytometry)	Decrease	0.001	Decrease	NA	Decrease	0.05
			Granzyme B expression in CD8+ T cells (flow cytometry)	NS		NS		NS
			Granzyme B expression in NK cells (flow cytometry)	NS		NS		NS
			Granzyme B expression in NKT cells (flow cytometry)	NS		NS		NS
			IL-6 level in serum	Decrease	0.01	NS		Decrease	0.05
			IL-8 level in serum	Decrease	0.05	NS		Decrease	0.01
			IFN-y level in serum	Decrease	0.01	NS		Decrease	0.05
			IL-1b level in serum	NS		NS		Decrease	0.05
			CRP level in serum	NS		NS		Decrease	0.05
			TNFα level in serum	NS		NS		NS
Kim et al. [ ]	2015	Forest adjuvant anti-cancer therapy to enhance natural cytotoxicity in urban women with breast cancer: A preliminary prospective interventional study	NK cell number (CD3-CD56+)	Increase	0.01					Forest therapy enhances natural cytotoxicity in breast cancer patients by increasing NK cells and cytotoxic mediators.
			Perforin level in serum (ELISA)	Increase	0.02
			Granzyme B level in serum (ELISA)	Increase	0.02
Li et al. [ ]	2007	Forest bathing enhances human natural killer activity and expression of anti-cancer proteins	NK cell number and % (CD16+)	Increase	0.01					Forest bathing enhances NK cell activity and numbers in healthy male adults.
			Cytolytic NK cell activity (Cr-release assay)	Increase	0.01
			% of T cells (CD3+)	Decrease	NA
			% of perforin- expressing cells	Increase	0.01
			% of granzyme A/B- expressing cells	Increase	0.01
			% of granulysin-expressing cells	Increase	0.01
Li et al. [ ]	2008a	A forest bathing trip increases human natural killer activity and expression of anti-cancer proteins in female subjects	NK cell number and % (CD16+)	Increase	0.01					Forest bathing enhances NK cell activity and numbers in healthy female adults.
			Cytolytic NK cell activity (Cr-release assay)	Increase	0.01
			% of T cells (CD3+)	Decrease	0.05
			% of perforin- expressing cells	Increase	0.01
			% of granzyme A/B- expressing cells	Increase	0.01
			% of granulysin- expressing cells	Increase	0.01
Li et al. [ ]	2008b	Visiting a forest, but not a city, increases human natural killer activity and expression of anti-cancer proteins	NK cell number and % (CD16+)	Increase	0.01	NS		Increase	0.05	Forest bathing enhances NK cell activity and numbers in healthy adults.
			Cytolytic NK cell activity (Cr-release assay)	Increase	0.01	NS		Increase	0.05
			% of T cells (CD3+)	NS		NS
			% of perforin- expressing cells	Increase	0.01	NS
			% of granzyme A/B- expressing cells	Increase	0.01	NS
			% of granulysin- expressing cells	Increase	0.01	NS
Lyu et al. [ ]	2019	Benefits of a three-day bamboo forest therapy session on the psychophysiology and immune system responses of male college students	Cytolytic NK cell activity	Increase	0.05	NS			NA	Forest bathing in a bamboo forest enhances NK cell activity and percentages in healthy adults.
			% of NK cells (CD16+CD56+)	Increase	0.05	NS			NA
			Perforin level (ELISA)	Increase	0.05	NS			NA
			Granulysin level (ELISA)	NS		NS			NA
			Granzyme A/B level (ELISA)	Increase	0.05	NS			NA
Mao et al. [ ]	2012a	Effects of short-term forest bathing on human health in a broad-leaved evergreen forest in Zhejiang Province, China	IL-6 level in serum (radioimmunoassay)	NS		Increase	NA	Decrease	0.05	Forest bathing decreases pro-inflammatory cytokine levels (IL-6 and TNFα) in healthy young adults but has no effect on immune cell distribution.
			TNFα level in serum (radioimmunoassay)	Decrease	NA	Increase	NA	Decrease	0.05
			HCRP level in serum					NS
			% of B cells (CD5+CD19+)					Increase	0.05
			% of T cells (CD3+)					NS
			% of Th cells (CD3+CD4+)					NS
			% of cytotoxic T cells (CD3+CD8+)					NS
			% of NK cells (CD3-CD16+CD56+)					NS
Mao et al. [ ]	2012b	Therapeutic effect of forest bathing on human hypertension in the elderly	IL-6 level in serum (radioimmunoassay)	Decrease	0.05	NS		NS		Forest bathing decreases pro-inflammatory cytokine level (IL-6, but not TNFα) in elderly patients with hypertension.
Mao et al. [ ]	2012b		TNFα level in serum (radioimmunoassay)	NS		NS		NS
Mao et al. [ ]	2017	The salutary influence of forest bathing on elderly patients with chronic heart failure	IL-6 level in serum (ELISA)	NS		NS		Decrease	0.05	Forest bathing decreases pro-inflammatory cytokine level (IL-6, but not TNFα) in elderly patients with chronic heart failure.
			TNFα level in serum (ELISA)	NS		NS		NS
			HCRP level in serum	NS		NS		NS
Mao et al. [ ]	2018	Additive benefits of twice forest bathing trips in elderly patients with chronic heart failure	IL-6 level in serum (ELISA)	NS		NS		NS		A second forest bathing trip further decreases pro-inflammatory cytokine level (TNFα, but not IL-6) in elderly patients with chronic heart failure.
Mao et al. [ ]	2018		TNFα level in serum (ELISA)	Decrease	0.05	NS		Decrease	0.05
Seo et al. [ ]	2015	Clinical and immunological effects of a forest trip in children with asthma and atopic dermatitis								Forest environment improves clinical symptoms in asthmatic children.
			Forced vital capacity (spirometry, FCV)	Increase	0.05
			Fractional exhaled nitric oxide (FeNO)	Decrease	NA
Seo et al. [ ]	2015	Clinical and immunological effects of a forest trip in children with asthma and atopic dermatitis								Forest environment improves clinical symptoms and has immunological effects in chronic allergic skin disease.
			Atopic dermatitis index (SCORAD)	Decrease	NA
			Thymus and activation-regulated chemokine/CCL17 level	NS
			Macrophage-derived chemokine/CCL22 level	Decrease	0.01
Tsao et al. (forest workers) [ ]	2018	Health effects of a forest environment on natural killer cells in humans: an observational pilot study	% of NK cells in blood (CD3-CD56+)					Increase	0.05	Living in a forest environment increases NK cell percentage, but not the amount of activated NK cells.
Tsao et al. (forest workers) [ ]	2018		% of activated NK cells in blood (CD3-CD56+CD69+)					NS
Tsao et al. (forest bathing) [ ]	2018	Health effects of a forest environment on natural killer cells in humans: an observational pilot study	% of NK cells in blood on d5	NS						Short-term forest trip enhances fraction of activated NK cells in healthy adults, and effect lasts for at least 4 days.
			% of activated NK cells in blood on d5	Increase	0.01
			% of NK cells in blood on d9 (4 days after intervention)	NS
			% of activated NK cells in blood on d9 (4 days after intervention)	Increase	0.01

Li et al. [ ]	2009	Effect of phytoncide from trees on human natural killer cell function	Cytolytic NK cell activity (Cr-release assay)	Increase	0.05					Phytoncide exposure enhances NK cell activity and % in healthy adults.
			% of NK cells (CD16+)	Increase	0.01
			% of T cells (CD3+)	Decrease	0.01
			% of perforin- expressing cells	Increase	0.05
			% of granzyme A/B- expressing cells	Increase	0.01 0.05
			% of granulysin- expressing cells	Increase	0.05

Kiecolt-Glaser et al. [ ]	2008	Olfactory influences on mood and autonomic, endocrine and immune function	Delayed hypersensitivity to candida (DTH)	Increase	NA	Increase	NA	Decrease	= 0.02 (lavender) = 0.06 (lemon)	Greater DTH response after water inhalation indicates better immune response than in fragrance groups, but no difference in cytokine levels detectable.
			PBL proliferation (blastogenesis)					NA*
			IL-6 level in PBLs (ELISA)					NS
			IL-10 level in PBLs (ELISA)					NS
Komori et al. [ ]	1995	Effects of citrus fragrance on immune function and depressive states	Deviation from normal CD4/CD8 ratio	Decrease	NA					Citrus fragrance has a beneficial effect on immune cell distribution in depressive patients and can reduce the dose antidepressants needed.
Komori et al. [ ]	1995		Deviation from normal NK cell activity (Cr-release assay)	Decrease	NA
Trellakis et al. [ ]	2012	Subconscious olfactory influences of stimulant and relaxant odors on immune function	IL-8 level in serum (ELISA)					NS		No significant effect of any stimulatory or relaxing fragrance exposure on immune parameters in healthy adults.
			IL-6 level in serum (ELISA)					NS
			TNFα level in serum (ELISA)					NS
			CCL3 (MIP-1a) level in serum (ELISA)					NS
			CCL4 (MIP-1b) level in serum (ELISA)					NS
			CCL5 (RANTES) level in serum (ELISA)					NS
			CXCL8 (IL-8) release by neutrophils					NS

Gaisberger et al. [ ]	2012	Effects of ionized waterfall aerosol on pediatric allergic asthma	IL-5 level in serum (ELISpot)	Decrease	0.05	NS		Decrease	NS	Exposure to waterfalls reduces pro-inflammatory cytokines and allergic asthma symptoms, enhances lung function and induces Treg cells.
			IL-10 level in serum (ELISpot)	Increase	0.05	NS		Increase	NS
			IL-13 level in serum (ELISpot)	Decrease	0.01	Decrease	0.01	NS
			IL-10 expression (PCR)	Increase	NA	Increase	NA	NS
			IL-13 expression (PCR)	Decrease	NA	NS	NA	Decrease	0.05
			IFNg expression (PCR)	Increase	NA	Increase	NA	NS
			Treg cells (%)	Increase	0.01	Increase	0.05	NS
			Eosinophilic cationic protein (ECP) levels in serum	Decrease	0.05	NS		NS
			Fractional exhaled nitric oxide (FeNO) at d20	Decrease	0.001	Decrease	0.001		NA
			Fractional exhaled nitric oxide (FeNO) at d80	Decrease	0.01	NS			NA
			Peak expiratory flow rate (PEF)	Increase	0.01	Increase	0.01		NA
			Other spirometric parameters (FEV, FEV%FVC, FEF25, FEF50, MMEF2575)	Increase	0.05 0.01	NS			NA
Grafetstätter et al. [ ]	2017	Does waterfall aerosol influence mucosal immunity and chronic stress? A randomized controlled clinical trial	IgA level in saliva (d6)	Increase	NA	Increase	NA	Increase	= 0.001	Exposure to waterfalls activates the immune system and improves lung function.
			IgA level in saliva (d66)	Increase	NA	NS		Increase	0.05
			Peak expiratory flow rate (PEF) (d6)	Increase	= 0.023	Increase	NA	NS

3.4.2. Synthesis of Human Studies

The synthesis of human studies analysing the immunological effects of forest bathing points to largely positive evidence of anti-inflammatory and anti-asthmatic effects along with a promising evidence of enhanced cytotoxicity stemming from increased NK cell levels or activities. However, the synthesis of anti-inflammatory effects was obscured by differing results derived from analysing cytokine levels, specifically IL-6 and TNFα. Some studies only observed an alteration in one of the cytokines and no change in the other, while other studies reported a change in the respective other cytokine value. Since the results reveal overall anti-inflammatory effects, the evidence base is still regarded as largely positive, but not entirely conclusive. Several forest bathing studies also measured immune cell subset distributions. While no significant changes in T cell numbers and/or percentages were observed, most studies showed an increase of NK cell levels along with elevated percentages of cells with cytotoxic content (perforin, granzyme A/B and granulysin).

Studies without control groups and/or without sufficient baseline values to adequately control for confounders were heavily represented among forest bathing studies. Almost half of the studies were carried out as one group pre-post intervention designs [ 52 , 53 , 54 , 55 , 56 , 57 ]; therefore, their findings have less strength but are backed up by similar results from the included CCT studies. Furthermore, a considerable number of forest bathing studies did not provide a thorough calculation of significances for certain outcome measures that were nevertheless interpreted by the study authors as showing an effect. Moreover, most studies comprised a low number of study participants (<30 subjects), which weakened the evidence base for the measured effects significantly. Only four forest bathing studies analysed larger group sizes [ 44 , 45 , 47 , 57 ]. One of them showed retrospective results from a big cohort of subjects living in a forest environment, but lacked baseline values of respective measures [ 57 ]. Three other studies with larger sample sizes either provided no pre-intervention data [ 44 ], no appropriate significance calculations [ 47 ] or ignored considerable baseline differences [ 45 ], which weakened their results. The findings on NK cell distributions were underlined by positive results from one laboratory experiment simulating BVOC exposure in natural environments [ 58 ]; however, this study provided no control group and must therefore be interpreted cautiously. Overall, the evidence base for the effects of forest bathing on immune functioning can be regarded as promising, despite substantial study design shortcomings.

The three studies analysing fragrance inhalation showed highly heterogeneous results that ranged from beneficial immune responses to no measurable effects at all. The different study designs and measured parameters resulted in differing outcomes, which barely suffice to formulate overall tendencies. It is noteworthy that the two studies describing certain positive effects were relatively old [ 59 , 60 ] and one of them used out-dated methods (for details, see Supplementary Material ) [ 59 ]; accordingly, these results must be questioned in terms of reliability and validity.

Lastly, the two studies analysing the effects of waterfall exposure on immunological health provided good study designs with appropriate controls and group sizes as well as methodologically transparent approaches [ 34 , 35 ]. Thus, their results showing anti-inflammatory and anti-allergic outcomes as well as beneficial clinical outcomes provided a reliable evidence base which remains to be confirmed by a greater number of studies.

In conclusion, human studies provide a promising evidence base for immunomodulatory effects following exposure to natural environments, though general shortcomings in the study designs weaken their soundness.

3.5. Outcomes and Synthesis of Animal Studies

3.5.1. outcomes of animal studies.

Most animal studies examined the effects of phytoncide or aroma inhalation on a pre-induced immune response. Experimental parameters analysed were levels of various cytokines and/or antibodies in sera and/or bronchoalveolar lavage fluids (BALF) of the respiratory tract, leukocyte numbers (mostly neutrophils, eosinophils, macrophages and lymphocytes) as well as histological or clinical symptoms such as cellular or structural changes, inflammatory cell infiltrations into lung tissue or respiratory markers. Some studies assessed several outcome measures. Overall, a positive effect was observed on most immunological parameters and only one study showed no significant changes. An overview of outcomes from animal studies is presented in Figure 3 .

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Overview of outcomes from animal studies.

By measuring a decrease in pro-inflammatory and/or an increase in anti-inflammatory (IL-10) cytokines as well as a reduced number of leukocytes, 13 animal studies reported anti-inflammatory, anti-allergic and/or anti-asthmatic effects following exposure to natural substances. All studies analysing BVOC [ 62 , 64 , 75 ] and eucalyptol [ 65 , 66 , 74 ] inhalation attested to protective and therapeutic anti-inflammatory effects of these substances in asthma- or allergy-challenged animals. The results for limonene were more heterogeneous, with four out of five studies observing potentially beneficial, anti-inflammatory effects in challenged animals [ 67 , 68 , 70 , 73 ], while one study showed no significant effects of limonene inhalation [ 69 ]. The mixture of limonene and ozone inhalation was able to protect from the adverse effects elicited by inhalation of only ozone in two studies [ 69 , 70 ]. Furthermore, inhalation of linalool was able to change the immune cell distribution of previously stressed rats, as one study reported [ 72 ]. Another study observed that exposure to certain fragrances was able to induce a general immune activation, which they diagnosed by measuring the number of plaque-forming cells in spleen and the thymic weight [ 71 ].

The findings of all animal studies are summarised in Table 6 .

Outcomes of animal studies. Significances are given with p < 0.05, p < 0.01 and p < 0.001; NS = not significant, NA=not applicable. A non-significant trend is described as “Decrease/Increase, NS”. If significances are not given, it is described as “Decrease/Increase, NA”.

				Outcome
Main Author	Year	Title	Measure	Pre-treatment	-Value	Intervention (Compared to Pre-treatment)	-Value	Conclusion	Comment

Ahn et al. [ ]	2018a	Alleviation effects of natural volatile organic compounds from Pinus densiflora and Chamaecyparis obtuda on systemic and pulmonary inflammation	IgE level in serum (ELISA)	Increase	0.05	Decrease	0.05	BVOCs (VOCCo, VOCPd) excert anti-inflammatory effects in mice.
			Prostaglandin E2 (PGE2) level in serum (ELISA)	Increase	0.05	Decrease	0.05
			COX-2 mRNA expression in PBMCs	Increase	0.05	Decrease	0.05
			TNFα mRNA expression in PBMCs	Increase	0.05	Decrease	0.05
			IL-1b mRNA expression in PBMCs	Increase	0.05	Decrease	0.05
			IL-13 mRNA expression in PBMCs	Increase	0.05	Decrease	0.05
			COX-2 mRNA expression in lung tissue	Increase	0.05	Decrease	0.05
			NF-kB mRNA expression in lung tissue	Increase	0.05	Decrease	0.05
			TNFα mRNA expression in lung tissue	Increase	0.05	NS
			COX-2, NF-kB, IL-1b, TNFα, IL-13 mRNA in BALF cells	Increase	0.05	Decrease	0.05
Ahn et al. [ ]	2018b	Anti-asthmatic effects of volatile organic compounds from Chamaecyparis obtusa, Pinus densiflora, Pinus koraiensis, and Larix kaempferi wood panels	Thickening of bronchiolar wall (hypertrophy)	Increase	NA	Decrease	NA	BVOCs (VOCCo, VOCPd, VOCPk, VOCLk) excert anti-allergic effects in asthmatic mice.
			IL-4 level in serum (ELISA)	Increase	0.05	Decrease	0.05
			TNFα level in serum (ELISA)	Increase	0.05	Decrease (C. obtusa)	0.05
			IL-4 mRNA expression in bronchioles	Increase	0.05	Decrease	0.05
			IL-5 mRNA expression in bronchioles	Increase	0.05	NS
			IL-9 mRNA expression in bronchioles	Increase	0.05	Decrease (C. obtusa)	0.05
			IL-13 mRNA expression in bronchioles	Increase	0.05	Decrease	0.05
Yang et al. [ ]	2015	Estimation of the environmental effect of natural volatile organic compounds from Chamaecyparis obtusa and their effect on atopic dermatitis-like skin lesions in mice	IgE level in serum	Increase	0.05	Decrease	0.05	Exposure to BVOCs (C. obtusa) ameliorates inflammatory skin reactions in mice with atopic dermatitis.
			Mast cell infiltration into skin lesions	Increase	0.05	Decrease	0.05
			IL-1b mRNA expression in skin lesions	Increase	0.05	Decrease	0.05
			IL-6 mRNA expression in skin lesions	Increase	0.05	Decrease	0.05

Bastos et al. [ ]	2011	Inhaled 1,8-Cineole reduces inflammatory parameters in airways of ovalbumin-challenged guinea pigs	TNFα level in BALF (ELISA)	Increase	0.05	Decrease	NS	Eucalyptol (1,8-cineol) inhibits antigen-induced airway inflammation in guinea pigs.
			IL-1b level in BALF (ELISA)	Increase	0.05	Decrease	NS
			IL-10 level in BALF (ELISA)	Decrease	0.05	Increase	NS
			Leukocyte number in BALF (eosinophils and neutrophils)	Increase	0.05	Decrease	0.05
			MPO activity	Increase	0.05	Decrease	0.05
Kennedy-Feitosa et al. [ ]	2019	Eucalyptol promotes lung repair in mice following cigarette smoke-induced emphysema	TNFα level in lung tissue	Increase	0.01	Decrease	0.01	Eucalyptol reduces pro-inflammatory cytokines and neutrophil activation marker (MPO) after lung damage by cigarette smoke.
			IL-1b level in lung tissue	Increase	0.01	Decrease	0.05
			IL-6 level in lung tissue	Increase	0.01	Decrease	0.01
			TGFß-1 level in lung tissue	Increase	0.05	Decrease	0.05
			MPO activity in lung tissue	Increase	0.01	Decrease	0.05
Lee et al. [ ]	2016	Effect of 1,8-cineol in -stimulated bronchial epithelial cells and mouse model of asthma	IL-4 level in BALF (ELISA)	Increase	0.01	Decrease	0.05	Eucalyptol reduces pro-inflammatory cytokine expression (IL-4, IL-13, IL-17A) in house dust mite-allergic/asthmatic mice.
			IL-13 level in BALF (ELISA)	Increase	0.05	Decrease	0.05
			IL-17A level in BALF (ELISA)	Increase	0.05	Decrease	0.05
			Neutrophil number in BALF	Increase	0.05	Decrease	0.05
			Eosinophil number in BALF	Increase	0.05	Decrease	0.05
			Lymphocyte number in BALF	Increase	0.05	Decrease	0.05
			Der p-specific IgG1 in serum (ELISA)	Increase	0.01	Decrease	0.05
			Airway restriction (Penh)	Increase	0.01	Decrease	0.05

Bibi et al. [ ]	2015	Treatment of asthma by an ozone scavenger in a mouse model	Aldehyde (ozone oxydation product) levels in BALF	Increase	NA	Decrease	NA	Prophylactic limonene inhalation protects against allergic asthma in mice.
			Aldehyde (ozone oxydation product) levels in lung tissue	Increase	NA	Decrease	NA
			Aldehyde (ozone oxydation product) levels in spleen	Increase	NA	Decrease	NA
			Neutrophil number in BALF	Increase	NA	Decrease	0.05
			Eosinophil number in BALF	Increase	NA	NS
			Infiltration of inflammatory cells into lung tissue	Increase	NA	Decrease	NA
Hirota et al. [ ]	2012	Limonene inhalation reduces allergic airway inflammation in -treated mice	Der f-specific IgG in serum (ELISA)	Increase	0.001	Decrease	0.01	Limonene reduces pro-inflammatory cytokines and cell numbers in mice pre-sensitized to house dust mite allergen.
			Total IgE in serum (ELISA)	Increase	NS	Decrease	NS
			Eosinophil number in BALF	Increase	0.001	Decrease	0.001
			Lymphocyte number in BALF	Increase	0.001	Decrease	0.05
			Neutrophil number in BALF	Increase	0.001	Decrease	0.05
			Macrophage number in BALF	Increase	0.001	Decrease	0.05
			IL-5 level in BALF	Increase	0.001	Decrease	0.001
			IL-13 level in BALF	Increase	0.001	Decrease	0.001
			Eotaxin level in BALF	Increase	0.001	Decrease	0.001
			MCP-1 level in BALF	Increase	0.001	Decrease	0.001
			TGF-b level in BALF	Increase	0.001	Decrease	0.05
			IFNy level in BALF	Decrease	0.01	Increase	0.05
			Bronchorestriction with Ach	Increase	0.01	Decrease	0.01
Keinan et al. [ ]	2005	Natural ozone scavenger prevents asthma in sensitized rats						Limonene reduces inflammatory cell infiltrates into lung tissue and improves airway restriction in lungs of rats with allergic asthma.
			Inflammatory cell infiltrates	Increase	NA	Decrease	NA
			Airway restriction (Penh)	Increase	NA	Decrease	NA
								Eucalyptol reduces inflammatory cell infiltrates into lung tissue, but to a lesser extent than limonene, but does not improve airway restriction.
			Inflammatory cell infiltrates	Increase	NA	Decrease	NA
			Airway restriction (Penh)	Increase	NA	NS

Hansen et al. [ ]	2013	Adjuvant and inflammatory effects in mice after subchronic inhalation of allergen and ozone-initiated limonene reaction products						Limonene inhalation has no significant effect on inflammatory response in pre-sensitized mice.
			OVA-specific IgE in serum (ELISA)	Increase	NA	NS
			Eosinophil number in BALF	NS		NS
			Lymphocyte number in BALF	Increase	NA	NS
			Neutrophil number in BALF	Increase	NA	NS
			Macrophage number in BALF	Increase	NA	NS
								Limonene/ozone mixture reduces allergen-specific reactions in pre-sensitized mice.
			OVA-specific IgE in serum (ELISA)	Increase	NA	Increase	0.05
			Eosinophil number in BALF	Increase	NA	Decrease	0.05
			Lymphocyte number in BALF	Increase	NA	Decrease	NS
			Neutrophil number in BALF	Increase	NA	Decrease	0.05
			Macrophage number in BALF	Increase	NA	NS
Hansen et al. [ ]	2016	Limonene and its ozone-initiated reaction products attenuate allergic lung inflammation in mice						Limonene potentially reduces airway inflammation in allergic mice, however no significances given.
			OVA-specific IgE in serum (ELISA)	Increase	NA	Decrease	NA
			OVA-specific IgG1 in serum (ELISA)	Increase	NA	NS
			Eosinophil number in BALF	Increase	NA	NS
			Lymphocyte number in BALF	Increase	NA	Increase	NA
			Neutrophil number in BALF	Increase	NA	Decrease	NA
			Macrophage number in BALF	Increase	NA	Decrease	NA
			IL-5 expression in BALF	Increase	NA	Decrease	NA
								Limonene/ozone mixture potentially attenuates allergic inflammation and ozone-induced pulmonary irritation in allergic mice.
			OVA-specific IgE in serum (ELISA)	Increase	NA	Decrease	NA
			OVA-specific IgG1 in serum (ELISA)	Increase	NA	Increase	NA
			Eosinophil number in BALF	Increase	NA	Decrease	0.05
			Lymphocyte number in BALF	Increase	NA	Decrease	NA
			Neutrophil number in BALF	NS		NA
			Macrophage number in BALF	Increase	NA	Decrease	NA
			IL-5 expression in BALF	Increase	NA	Decrease	NA

Nakamura et al. [ ]	2009	Stress repression in restrained rats by R-(-)-linalool inhalation and gene expression profiling of their whole blood cells	% of neutrophils	Increase	0.05	Decrease	NA	Linalool inhalation reverts stress-induced changes in neutrophil and lymphocyte fractions.
Nakamura et al. [ ]	2009		% of lymphocytes	Decrease	0.05	Increase	NA

Fujiwara et al. [ ]	1998	Effects of a long-term inhalation of fragrances on the stress-induced immunosuppression in mice						Exposure to natural fragrances reverses stress-induced thymic involution and activates the immune system.
			Lemon inhalation	Decrease	0.05	Increase	0.05
			Oakmoss inhalation	Decrease	0.05	Increase	0.05
			Labdanum inhalation	Decrease	0.05	Increase	0.05
			Tuberose inhalation	Decrease	0.05	Increase	0.05

			Lemon inhalation	Decrease	0.05	Increase	0.05
			Oakmoss inhalation	Decrease	0.05	Increase	0.05
			Labdanum inhalation	Decrease	0.05	Increase	0.05
			Tuberose inhalation	Decrease	0.05	Increase	0.05

3.5.2. Synthesis of Animal Studies

Overall, animal studies point to largely coherent and unambiguous evidence for anti-inflammatory effects of phytoncide inhalation in immune-challenged animals. Most experimental setups could easily be compared to each other, since they were relatively homogeneous concerning their methodological approaches, sample sizes and outcome measures. Many studies examined a broad range of inflammatory cytokines and specific antibodies, some measuring both mRNA expression and protein levels. All studies reported widely concordant outcomes, as almost all interventions were able to reverse the inflammation induced by the distinct pre-treatments. Differences were found in the statistical analysis and evaluation of results, with some studies providing rigorous statistical significance calculations and others none. Especially the studies examining BVOC and eucalyptol inhalation comprised a good study design and statistical evaluation, rendering strong evidence for the beneficial effects of these treatments.

Out of the three studies examining limonene inhalation alone, two lacked significance calculations [ 67 , 73 ] while one provided good statistical evaluations [ 68 ]. This made it difficult to reliably conclude on the effects observed from limonene inhalation, but points to a positive immune response derived from these experiments.

In contrast, two studies analysing the combined effects of limonene and ozone inhalation in pre-sensitised animals failed to provide essential baseline values before sensitisation, did not show any sensitisation-only control values and lacked significances and statistical comparisons between relevant groups [ 69 , 70 ]. These extensive shortcomings made it impossible to draw any conclusions based on these experiments.

Lastly, single experiments measured the effects of linalool [ 72 ] and fragrance [ 71 ] inhalation, respectively. One of them used out-dated methods (see Supplementary Material for further details), which made the results less robust [ 71 ].

In conclusion, animal studies included in this review provide a solid evidence base for anti-inflammatory, anti-asthmatic and anti-allergic effects upon inhalation of nature-derived substances, especially BVOCs and eucalyptol.

4. Limitations of the Review

Limitations are found in the study selection process, which might be biased due to the interdisciplinarity of the topic and the difficulties generated in performing a fitting keyword search. Studies in the field of immunological health and nature have yet no common narrative, making it difficult to formulate a search string that selectively targeted studies from different disciplines. Also the variety of interventions and methodological approaches made it challenging to incorporate all possible wordings into one comprehensive search string. Especially within the field of animal studies, many studies focused on the analysis of a single substance and only included this specific term in their titles and keywords. This problem was handled by including snowballing as additional search strategy. Nevertheless, it cannot be ruled out that individual studies which would also meet this review’s inclusion criteria are missing from the present review. Furthermore, due to the large number of articles resulting from the initial keyword search, it was not possible to include more than two databases in the search. However, included databases gave entirely overlapping outputs, with Scopus being the database having most relevant hits.

Association studies were excluded from this review, since they require different quality assessment approaches and a separate synthesis, which was beyond the scope of the review. Nevertheless, the field provides a high amount of large and rigorously designed population-based association studies that render compelling insights into and provide supplementary evidence for nature’s effect on the immune system. It therefore remains an open task to systematically assess association studies published on this topic and evaluate their outcomes, which could subsequently be merged with the final synthesis of the review at hand.

5. Discussion

Until recently, scientific studies on nature and human health have largely been separated into traditional research fields such as environmental science, ecology, biology, geography, landscape architecture, medicine, psychology, epidemiology and public health. This has generated an impressive amount of data that is now starting to be fruitfully brought together in a holistic perspective to stimulate a broad, interdisciplinary research agenda on environmental health. A considerable number of reviews have emerged that illuminate connections between nature and many human health challenges [ 11 , 76 , 77 , 78 ]; however, studies focusing on immunological health benefits have so far been underrepresented. This review examined both human and animal studies and found a promising evidence base for immunomodulatory effects following exposure to natural volatile substances or environments, comprising anti-inflammatory, anti-asthmatic, anti-allergic and cytotoxic responses from inhalation of diverse nature-derived compounds.

Whether or not natural environments have the potential to alleviate or even prevent immunological health problems remains an open question that needs more investigation from a multi-dimensional perspective. Animal studies are a strong tool to formulate a robust initial starting point and can be used to back up findings from studies with human subjects. In this review they represent an important data source concerning changes in expression levels of immunological key molecules resulting from the inhalation of biogenic substances. They are used to dissect mRNA and protein expression of inflammatory molecules in various tissues (lung, bronchioles, skin) and not only in blood, as it is commonly done in human experiments. The advantage of animal experiments is that they can easily screen a set of potential hypotheses with relatively low effort and be carried out in standardised, controllable conditions. Unequivocally, translating results into the human setting is challenging, since the standardised experimental setups do not correspond to the multi-faceted aspects of human life. Further, the ethical aspects of using experimental animals need to be diligently balanced with the scientific gains and alternatives considered whenever possible. At present, laboratory experiments are fundamental in disentangling mechanistic pathways and establishing a data base that can eventually be tested in the human system. The positive evidence base derived from animal experiments included in the present review supports the notion that immune functioning might represent a direct, central pathway of how nature and health are connected.

5.1. A Baseline for Future Research

Next to providing a comprehensive literature overview, the goal of this review was to define a baseline of existing data for future research. However, since most included studies diverged in their methodological approaches and only performed a superficial screening of varying parameters, this baseline cannot be explicitly defined. Animal and human experiments analysed largely distinct parameters. While animal studies screened a wide range of different cytokines along with measuring detailed leukocyte subset distributions, most human studies did not provide such a thorough analysis of inflammatory parameters and focused more on specific cytokines and cytotoxic mediators. Thus, the human study outcomes are relatively fragmented and lack a comprehensive insight into the distribution of other immune cell types and properties. Therefore, data derived from included human and animal studies in this review can hardly be linked. Nevertheless, a clear anti-inflammatory and cytotoxic tendency can be observed in the majority of studies. Decreased expression levels of many pro-inflammatory molecules in various tissue and blood samples along with an infiltration of leukocyte subsets and an increase of NK cell activity and release of cytotoxic granules are results that may serve as a baseline for further studies.

5.2. Study Shortcomings and Recommendations for Future Study Designs

Overall, the synthesis of study findings carried out in this review presents some promising evidence for the positive influence of nature exposure on various aspects of immune functioning. However, considerable shortcomings in the design and conduct especially of included human studies weaken their solidity. Most studies examined only one independent replicate (trials were carried out once), leaving the study inherently prone to random and systematic errors that can only be ruled out by trial repetitions (at least three independent replicates). Moreover, the high number of human studies completely lacking controls gives rise to major concerns regarding the reproducibility and reliability of study outcomes. It has been shown that “within-subject” studies are susceptible to bias since an individual’s initial physiological outcome value can influence the extent and direction of post-intervention responses [ 79 ]. Furthermore, most studies neither monitored environmental conditions nor adjusted for potential changes in airborne parameters such as temperature, humidity or BVOC concentrations, which makes it hard to account for individual parameters that might influence study outcomes. The majority of animal studies did not show comparable shortcomings; however, selected studies lacked important baseline values as well as statistical comparisons between relevant groups. In general, included animal trials were also not repeated to generate three independent replicates, which again represents a main drawback concerning the solidity of outcomes.

Ideally, future studies should encompass relatable animal and human experiments including sufficient and adequate controls (placebo controls, controls of external conditions as well as positive and negative control groups). Moreover, they should calculate effect sizes and provide dose-response relationships. In order to guarantee outcome reproducibility, results should be consolidated by a minimum of three trial repetitions. Along with improving the rigor of study designs, the study field should be expanded to bigger group sizes and diverse environments and use more in-depth, state-of-the art analytical methods such as next generation sequencing and big data technologies.

5.3. What Is the Optimal Type, Length, Season and Dosage of Nature Exposure?

Studies included in this review originate from different research fields and approach the main question from distinct scientific angles. Although the included studies cover different target groups, exposure types and durations, some essential questions concerning the maximal efficacy of nature exposure still remain open. Which type of nature is best suited for governing positive immunoregulatory effects? How long should nature exposure last and which dosage do we need to ensure a prolonged, but safe, effect? When is the optimal timeframe for nature contact in order to gain the maximum effect?

A factor that might influence the efficacy and magnitude of immune response to natural environments is the type and variability of vegetation that humans are exposed to, also termed eco- or geodiversity [ 20 ]. This encompasses both diverse landscape types such as forests, meadows, mountains, coastal areas or oceans as well as the specific species that can be found in these habitats. Human studies in this review mainly analyse forest environments, but encompass a range of different forest types such as broad-leaved, coniferous or bamboo forests. Animal studies also highlight immunomodulatory properties of different BVOCs and natural fragrances, but fail to relate them to specific vegetation types in the natural world. Therefore, it cannot be concluded from the studies included here which type of nature is best at conferring immunological benefits. However, catalogues of different species’ BVOC emission rates from needles and leaves are available [ 80 , 81 ]. BVOC emission potentials depend on environmental factors such as temperature and light, and species-specific factors such as plant age, developmental stage, intercellular CO 2 concentration, stomatal conductance, leaf structure and gas storage potential [ 31 , 82 ]. Seasonal and diurnal variability have also been observed, and summer seemed to be the best time for using forest environments for medical purposes due to highest temperatures and best light conditions [ 31 , 82 ]. Preliminary evidence points to a characteristic daily emission pattern which might at least apply on clear and calm days, while cloudy and windy conditions appear to be least beneficial for the uptake of BVOCs from forest environments [ 31 , 82 ], but further research is necessary to link these findings with policies that promote public health gains.

Concerning the duration of exposure, this review included studies with exposures ranging from a few hours to several days and weeks. Animal studies were especially useful to elucidate longer exposures of up to four months. However, no conclusion on minimal durations or dosage of nature exposure can be drawn due to the various experimental setups and substances tested. Along with the missing calculation of effect sizes, exposure characteristics need to be analysed in much more detail in order to correctly interpret the study results. Very limited research has so far been carried out to address the question of explicit exposure-response relationships between nature and human health, and no studies included in this review provided relevant answers on this topic. However, some large-scale, population-based research has tried to establish an association between the duration of nature exposure and observed health effects. One study showed that spending a minimum of two hours a week in nature improved overall health and wellbeing, with positive associations peaking at approximately four hours of exposure [ 83 ]. Another study examining the associations between frequency, duration and intensity of nature exposure observed a reduction in the prevalence of depression and high blood pressure following nature visits longer than 30 min a week [ 84 ]. However, these studies can only provide fractional answers and do not address immunological responses at all.

Another interesting question relates to the optimal exposure time point in life. The review at hand includes studies with adults, elderly and children, but none of the studies compared different exposure timeframes in different target groups; thus, this question cannot be answered here. However, association studies provide evidence for optimal time windows of nature exposure concerning immunological effects. Some studies show that very early exposures during pregnancy and childhood exhibit a greater immunomodulatory effect than exposures later in life [ 85 , 86 ]. Other studies report that exposures during late childhood up to the age of 10–15 years are associated with a lower risk of developing multiple sclerosis [ 87 , 88 ]. However, it seems that later exposures during adult life are also beneficial for certain immune parameters such as the immunoregulatory capacity of helminth infections [ 89 ]. To gain profound knowledge on the optimal exposure time point in life, longitudinal research monitoring immunological effects over longer timespans in different target groups is needed.

5.4. Understanding Biomedical Mechanisms

A wide range of studies exists that describes immunomodulatory effects of natural substances in vitro or in vivo by other administrative pathways than mere inhalation. Recently, the main molecular targets of terpenes in inflammatory diseases have been summarised and categorised into six groups [ 22 ]: inflammatory mediators (interleukins, TNFα, NO and COX2), transcription factors (NF-κB, Nrf2), signal transduction molecules (MAPK signalling molecules such as ERK, p38, JNK, but also STAT3, TRPVs, CB(2)R), oxidative stress (ROS, H 2 O 2 ) and autophagy (by targeting apoptotic genes). Disentangling key molecular components and action pathways provides important information for understanding the biomedical mechanisms of how nature affects the immune system, which is essential for its effective and targeted application. However, most studies used parenteral, oral or topical administration, which possibly increases effect sizes compared to studies set in natural environments. Therefore, it remains an open task to verify this evidence in more natural interventions that mimic real life exposures. The review at hand focuses on studies that only use inhalation of volatile substances as administrative pathway. Advantages of this approach are a low implementation threshold and a relatively easy transferability into therapy and policy measures. However, smaller and less coherent outcomes stemming from experiments performed in natural environments should not be confused with evidence obtained from invasive administrations. The challenge of the former will be to define effect sizes and molecular action pathways as clearly and in as detailed a manner as in invasive drug studies.

5.5. Nature-Based Clinical Applications

Considering the wide range of potential health benefits that nature provides, possibilities of how to effectively harvest these natural goods for future therapeutic applications can be envisioned. Owing to the rapid rise of diseases related to misled immunoregulation and the frequent severe side effects of currently used immunomodulatory drugs [ 90 , 91 ], there is a growing need for discovering new therapeutic options that are better tolerated. Nature-based interventions might represent such an option; however, potential adverse effects need to be considered when using nature in therapeutic and preventive clinical applications or implementing it in policy recommendations. Many terpenes are not harmful themselves, but can easily oxidise upon air exposure and create allergenic or inflammatory secondary molecules. One study reported irritations of the respiratory tract in mice after exposure to oxidation products from α-pinene and d-limonene [ 92 ]. Another study analysing the association between indoor VOCs and lung function reported α-pinene as one of 10 substances negatively influencing human lung function [ 93 ]. Auto-oxidation of various terpenes such as α- and β-pinene, limonene, camphor and β-phellandrene has also been observed to have negative allergenic effects on atopic dermatitis [ 94 , 95 , 96 ]. Thus, the observed adverse effects are concentration- and exposure-dependent, and call for a detailed evaluation of the safe concentration range of terpenes. Furthermore, the use of terpenes through “milder” exposure routes such as forest bathing or nature trips may constitute a potentially safer therapeutic strategy than their direct intake or skin application. Considering the small amount of data that exists on the potential adverse effects of volatile biogenic substances, it is yet too early to draw any conclusion from these studies. Nevertheless, the synthesis of the studies included in this review supports the notion that breathing in nature-derived compounds is overall beneficial for reducing inflammation and promoting immune homeostasis.

Besides the possible clinical use of nature, the findings of the studies in this review also point to potential benefits from promoting nature in official policy frameworks. Inhaling substances emitted from trees in close living proximity or being exposed to wood in daily housing environments display promising examples of co-benefits derived from sustainable developments tailored to support public health gains [ 13 , 36 ]. Possible policy measures could be to promote the conservation of natural environments, enforce the construction of houses from natural materials such as wood and enhance green infrastructure in urban regions. Green infrastructure could be a very effective and multifunctional measure to mitigate negative health impacts e.g., from urban heat islands in cities [ 36 ]. It may comprise vegetation planted in urban areas but also engineered structures that fulfil specific functions such as sustainable urban drainage systems (SUDS) [ 97 ], and may range from street trees, green roofs and walls, parks, allotment gardens to rain gardens and water basins. Pioneering policy recommendations have defined nature as a cost-effective planning tool for healthy cities [ 98 ]. Exposure to nature may therefore be an option to address a range of health challenges and be most effective if designed to harvest both direct as well as indirect benefits from nature (such as physical activity, social cohesion, improved mood, etc.).

Key environmental pressures, such as disruption of ecosystems, loss of biodiversity, habitat destruction, pollution and climate change are driven by human behaviour and threaten the resilience of natural systems [ 99 ]. Many studies have shown that these changes have a direct effect on living conditions on earth and significant implications for the public health agenda worldwide [ 2 , 11 ]. Human health is profoundly dependent on undamaged natural environments and functioning ecosystems that provide life supporting services and resources [ 1 ]. It is well known that climate change caused by human interventions in biogeochemical cycles negatively impacts ecological balances and concomitant ecosystem services [ 100 ]. The Lancet Countdown on Health and Climate Change has recently outlined pathways by which climate change will affect human health worldwide, spanning from exacerbation of existing health problems to introduction of new threats [ 10 ]. Anthropogenic climate change also has the potential to affect ecosystem services in terms of immunological health provisioning and regulation, especially by impacting the occurrence and spread of infectious diseases [ 10 , 101 ]. Examples are a change in the geographic range and resulting rise of vector-borne diseases [ 102 ], ancient viruses emerging from thawing permafrost [ 103 , 104 ] or the increase in allergenic pollen [ 105 ]. Mitigating climate change might therefore yield considerable co-benefits for human health, and joined-up policy making could be seen as a great opportunity for enforcing global health priorities in the 21st century. This study may contribute to a novel, uncommon argumentation in future nature protection and climate change mitigation debates and encourage green policy measures that benefit human and planetary health alike. At large, this review supports the notion that the conservation and creation of healthy human habitats along with the promotion of a nature-connected lifestyle create a new opportunity to support immunological health provisioning.

7. Conclusions

This systematic review gathers promising evidence that nature exposure influences measurable immunological parameters in healthy individuals as well as in people suffering from acute or chronic inflammatory conditions, and that inhaling certain volatile natural compounds can have a beneficial effect on the elicited immune response. According to the synthesis of the studies included in this review, nature exposure supports immunological homeostasis and might offer promising strategies for therapeutic and preventive clinical use. However, there is a lack of studies that rigorously address questions of selectivity, effectivity or adverse effects deriving from nature exposure, let alone providing mechanistic pathway analyses or a solid calculation of effect sizes. This is highly necessary to guarantee outcome reproducibility and safety of nature-based therapies for future broader applications. There is a need for expanding the study field to a larger scale and bigger study cohorts, including different study populations and environments, a standardised control for confounders and environmental conditions as well as the use of more in-depth, state-of-the-art analytical methods and tools. This is essential to draw adequate conclusions and envision a future potential for nature exposure in immunological disease prevention or treatment.

Supplementary Materials

The following are available online at https://www.mdpi.com/1660-4601/18/4/1416/s1 , Table S1: Risk of bias assessment of animal intervention studies following the SYRCLE guidelines.

Author Contributions

Each author made substantial contributions to the study. Conceptualisation: L.A., S.S.C. and U.K.S.; methodology: L.A. and S.S.C.; data retrieval and curation: L.A.; assessment: L.A. and S.S.C.; formal analysis: L.A. writing: L.A., S.S.C. and U.K.S.; project administration and funding acquisition: U.K.S. All authors have read and agreed to the published version of the manuscript.

This work was supported by the 15th of June Foundation, Denmark (grant number 2020-0374). The foundation had no involvement in the review.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Data availability statement, conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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a Department of Materials Science and Engineering, North Carolina State University, Raleigh, North Carolina 27695-7001, USA E-mail: [email protected]

b School of Chemistry, University College Dublin, Belfield, Ireland E-mail: [email protected]

c Electrochemical Process Engineering (EPE) Division, CSIR-Central Electrochemical Research Institute (CECRI), Karaikudi, Tamil Nadu 630003, India E-mail: [email protected]

d Department of Chemistry, University of California, Davis, California 95616, USA E-mail: [email protected]

e Fachbereich Chemie, Universität Konstanz, Universitätsstraße 10, 78457 Kostanz, Germany E-mail: [email protected]

Authors and editors alike want publications in the Journal of Materials Chemistry A to be visible to the community and to have strong impact in their respective fields and beyond. To help authors craft manuscripts that will be exciting, impactful and meaningful, and to withstand the test of time, the editors of J. Mater. Chem. A provide their tips and recommendations on structuring your paper to emphasise the new insights, rigour, and significance of your work.

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V. Augustyn, S. A. Cussen, S. Kundu, F. E. Osterloh and M. M. Unterlass, J. Mater. Chem. A , 2024, 12 , 17753 DOI: 10.1039/D4TA90097A

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Promoting your work to the materials community: editor top tips for
Authors and editors alike want publications in the Journal of Materials Chemistry A to be visible to the community and to have strong impact in their respective fields and beyond. To help authors craft manuscripts that will be exciting, impactful and meaningful, and to withstand the test of time, the editors of J. Mater.Chem.