Covid-19: Do many people have pre-existing immunity?
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m3563 (Published 17 September 2020) Cite this as: BMJ 2020;370:m3563Read our latest coverage of the coronavirus outbreak
All rapid responses
Dear Dr. Doshi,
I would like to point out recent literature and the relevance of recent outbreaks to argue that having reached herd immunity in New York, London, Stockholm or Madrid is not plausible, nor is an estimate of 10-20% for the herd immunity threshold (HIT) in these cities.
First of all, Lipsitch et al. [1] present an in-depth discussion as to why cross-reactive memory T cells may almost be certainly excluded to provide an intrinsic resistance to infection by SARS-CoV-2. They explain that such T cells may still have an important epidemiological consequence but which already appears in observational estimates of the basic reproduction number and thus does not modify estimates of HIT.
As for cross-reactive antibodies, a commonly cited value for their prevalence in the population is 10% [2-5], and considerably higher proportions would presumably interfere with the development of serologic assays [6], so that such a source of cross-immunity can also be disregarded from the point of view of estimating HIT. (Note that the study of Ng et al. [2] is not about T cells, as opposed to what the citation in your article indicates.)
Turning to real-world epidemiological data, as mentioned in your article, levels of seroprevalence were already found to be above or reasonably close to the cited lower guess of 10-20% for HIT [7] in New York, London, Stockholm and Madrid (23%, 18%, 12% and 11%, respectively [8-11]), and the true prevalence of past or active infection (together, 'prevalence of infection') is presumably even higher [12]. At the same time, these cities experienced or are currently experiencing a resurgence in new cases. Although a reliable estimate of the effective reproduction number would be difficult to associate with the resurgence in these cities, the fact of a resurgence under relatively weak but active preventive measures suggests that the prevalence of infection was considerably below HIT before the resurgence. This would imply that HIT would be considerably above 20%.
Note that preventive measures have either been obligatory as in New York, London and Madrid, or voluntary as in Stockholm. In fact, social distancing in Stockholm was not at all "poorly followed" in the spring [13-17], and mobility data suggest weaker but active preventive behaviour throughout the summer, extending into the autumn [18,19]. The resurgence in new cases presumably resulted from an intensification of social contacts in number or quality (end of the holiday season, beginning of school, more time spent in closed spaces as a result of autumn weather; note the earlier resurgence in Madrid). If this was so, lifting preventive measures before the new outbreaks would equally have led to a resurgence. In fact, an "intensification of social contacts" may very well include weaker compliance with preventive measures. (In the case of Madrid, the resurgence began soon after the lockdown ended [20].)
As a final example, the relatively well-documented case of Karachi suggests that current seroprevalence there, around 55%, should be relatively close to HIT: presumably, HIT may not be much lower but may still be higher than this registered value of seroprevalence [21]. The basic reproduction number seems unlikely to be so much different there, in comparison with New York, London, Stockholm or Madrid, that would allow for a much lower HIT in the latter cities.
To conclude, the prevalence of infection was presumably far from HIT in New York, London, Stockholm and Madrid before the recent outbreaks, and HIT may be supposed to be much higher than 20% in these cities. Although it's a bit more speculative, the above-presented considerations about cross-immunity, the case of Karachi, and the absence of a spontaneous reversal in the rate of spreading in the listed cities (i.e., the absence of a decrease in the effective reproduction number, as far as it can be estimated, before any intervention) make it implausible that HIT has been reached there during the present outbreaks until now (2020-10-15).
As a final remark, reaching even a 20% prevalence of infection is hardly acceptable in the case of a disease with an infection fatality rate above 0.1% [22,23], presumably much higher under an overloaded healthcare system [24], and with a considerable prevalence and severity of short- and long-term adverse health outcomes among the survivors [25,26]. At least, reaching such a prevalence of infection certainly seems to be unacceptable if there is a way of avoiding it without an economic collapse. The effectiveness of low-cost preventive measures against the spreading of COVID-19 definitely suggests this opportunity to be available [27,28].
Yours sincerely,
Gabor Drotos
I gratefully acknowledge useful comments from Konstantin Klemm on an earlier version of the text.
References:
[1] Lipsitch M, Grad YH, Sette A, et al. Cross-reactive memory T cells and herd immunity to SARS-CoV-2. Nat Rev Immunol 2020. https://doi.org/10.1038/s41577-020-00460-4
[2] Ng K, Faulkner N, Cornish G, Rosa A, Earl C, Wrobel A, et al. Pre-existing and de novo humoral immunity to SARS-CoV-2 in humans [preprint]. bioRxiv 2020. https://doi.org/10.1101/2020.05.14.095414
[3] Ma Z, Li P, Ikram A, Pan Q. Does Cross-neutralization of SARS-CoV-2 Only Relate to High Pathogenic Coronaviruses?. Trends in Immunology 2020;41:851-3. https://doi.org/10.1016/j.it.2020.08.002
[4] Jiang S, Du L. Effect of Low-Pathogenic Human Coronavirus-Specific Antibodies on SARS-CoV-2. Trends in Immunology 2020;41:853-4. https://doi.org/10.1016/j.it.2020.08.003
[5] Post N, et al. Antibody response to SARS-CoV-2 infection in humans: a systematic review. medRxiv 2020. https://doi.org/10.1101/2020.08.25.20178806
[6] Okba NMA, et al. Severe Acute Respiratory Syndrome Coronavirus 2-Specific Antibody Responses in Coronavirus Disease Patients. Emerg Infect Dis 2020;26:1478-88. https://doi.org/10.3201/eid2607.200841
[7] Lourenco J, Pinotti F, Thompson C, Gupta S. The impact of host resistance on cumulative mortality and the threshold of herd immunity for SARS-CoV-2 [preprint]. medRxiv 2020. https://www.medrxiv.org/content/10.1101/2020.07.15.20154294v1
[8] Rosenberg ES, Tesoriero JM, Rosenthal EM, et al. Cumulative incidence and diagnosis of SARS-CoV-2 infection in New York. Ann Epidemiol 2020;48:23-9.e4. pmid:32648546 https://doi.org/10.1016/j.annepidem.2020.06.004
[9] Public Health England. Sero-surveillance of COVID-19. 2020. https://www.gov.uk/government/publications/national-covid-19-surveillanc...
[10] Report: Påvisning av antikroppar efter genomgången covid-19 i blodprov från öppenvården (Delrapport1). Folkhälsomyndigheten, Stockholm, 2020-06-18. https://www.folkhalsomyndigheten.se/publicerat-material/publikationsarki...
[11] Pollán M, Pérez-Gómez B, Pastor-Barriuso R, et al., ENE-COVID Study Group. Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. Lancet 2020;396:535-44. pmid:32645347 https://doi.org/10.1016/S0140-6736(20)31483-5
[12] Altmann DM, Boyton RJ. SARS-CoV-2 T cell immunity: Specificity, function, durability, and role in protection. Science Immunology 2020;5:eabd6160. https://10.1126/sciimmunol.abd6160
[13] Erik J, Matej C. Impacts of COVID-19 on Public Transport Ridership in Sweden: Analysis of Ticket Validations, Sales and Passenger Counts. SSRN 2020. https://ssrn.com/abstract=3641536
[14] Dahlberg M, Edin PA, Grönqvist E, Lyhagen J, Östh J, Siretskiy A, Toger M. Effects of the COVID-19 Pandemic on Population Mobility under Mild Policies: Causal Evidence from Sweden. arXiv 2020. https://arxiv.org/abs/2004.09087
[15] Oberhammer J. Social-distancing effectiveness tracking of the COVID-19 hotspot Stockholm. medRxiv 2020. https://doi.org/10.1101/2020.06.30.20143487
[16] Kamerlin SCL, Kasson PM. Managing Coronavirus Disease 2019 Spread With Voluntary Public Health Measures: Sweden as a Case Study for Pandemic Control. Clin Infect Dis 2020;ciaa864. https://doi.org/10.1093/cid/ciaa864
[17] Irwin RE. Misinformation and de-contextualization: international media reporting on Sweden and COVID-19. Global Health 2020;16:62. https://doi.org/10.1186/s12992-020-00588-x
[18] Google COVID-19 Community Mobility Reports for Stockholm. Accessed 2020-10-15. https://www.google.com/covid19/mobility/
[19] Telia COVID-19 Mobility Analysis for Sweden. Accessed 2020-10-15. https://www.teliacompany.com/en/about-the-company/updates/mobility-analy...
[20] Fast-Track Cities initiative. International Association of Providers of AIDS Care. Accessed 2020-10-15. https://www.fast-trackcities.org/data-visualization/madrid-covid
[21] Rezwan F, Zaidi SK, Danish A, et al. Is Karachi Knocking at Herd Immunity? A Possible Reason for Decline in SARS-CoV-2 Infections. SSRN 2020. https://doi.org/10.2139/ssrn.3700931
[22] Ioannidis J. The infection fatality rate of COVID-19 inferred from seroprevalence data. medRxiv 2020. https://doi.org/10.1101/2020.05.13.20101253
[23] Cavataio J, Schnell S. Interpreting Sars-Cov-2 Fatality Rate Estimates - A Case for Introducing Standardized Reporting to Improve Communication. SSRN 2020. https://doi.org/10.2139/ssrn.3695733
[24] Wood RM, McWilliams CJ, Thomas MJ, et al. COVID-19 scenario modelling for the mitigation of capacity-dependent deaths in intensive care. Health Care Manag Sci 2020;23:315–324. https://doi.org/10.1007/s10729-020-09511-7
[25] Angelo C, Roberto B, Francesco L, for the Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19. JAMA 2020;324:603-605. https://doi.org/10.1001/jama.2020.12603
[26] Leung TYM, Chan AYL, Chan EW, et al. Short- and Potential Long-term Adverse Health Outcomes of COVID-19: A Rapid Review. Emerging Microbes & Infections 2020. https://doi.org/10.1080/22221751.2020.1825914
[27] Chu DK, et al. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis. The Lancet 2020;395:1973-87. https://doi.org/10.1016/S0140-6736(20)31142-9
[28] Dalton CB, Corbett SJ, Katelaris AL. COVID‐19: implementing sustainable low cost physical distancing and enhanced hygiene. Med. J. Aust. 2020;212:443-446.e1. https://doi.org/10.5694/mja2.50602
Competing interests: No competing interests
Dear Editor,
Several studies identified SARS-CoV-2 reactive T cells in uninfected individuals or people without exposure to the virus in various countries (1-5). The common limitation of these studies was the small numbers of donors contributing blood samples for the analyses (6). The most recent study (7) confirmed and extended these findings based on the analyses of 185 uninfected individuals. In unexposed to the SARS-CoV-2 individuals, the cross-reactive T cells against validated T cell epitopes were detected against 31% of HLA class I and 70% of HLA-DR peptide epitopes (7). Recognition frequencies against individual T cell epitopes in unexposed individuals were highly variable reaching 27% and 44% for the best-performing HLA class I and HLA-DR epitopes, respectively (7). Therefore, studies utilizing validated individual peptide epitopes as well as predicted or random SARS-CoV-2-derived peptide pools, consistently demonstrated pre-existing SARS-CoV2-directed T cell responses in unexposed as well as seronegative for SARS-CoV-2 individuals (1-7). The likely source of this phenomena is the immune cross-reactivity between human common cold coronaviruses and SARS-CoV-2 (1-8).
Preexisting T cell reactivity against SARS-CoV-2 varied in different countries, ranging from 18% in Sweden (5) to 51% in Singapore (4), suggesting the possible association between levels of preexisting T cell immunity and COVID-19 mortality rates in different countries. Currently available primary data on levels of preexisting T cell reactivity against SARS-CoV-2 and numbers of COVID-19 cases and death in five countries were obtained from original publications (1-5) and analyzed (https://doi.org/10.1101/2020.10.03.20206151 ). The significant inverse correlation (r = - 0.991) has been observed between the levels of pre-existing T cell reactivity against SARS-CoV-2 and mortality rates in different countries, which was most apparent when COVID-19 mortality rates are reported as the case fatality rates (CFR) independently defined for each country. The most extreme cases were represented by Singapore, where 51% of population manifested pre-existing T cell reactivity associated with the COVID-19 mortality rate of 0.05%, compared with Sweden, where 18% of population manifested preexisting T cell reactivity associated with the COVID-19 mortality rate of 6.35%.
Less significant inverse correlation between levels of preexisting SARS-CoV-2 reactive T cells and COVID-19 mortality per million population in different countries was observed. In two separate instances two countries manifesting similar levels of preexisting T cell reactivity against SARS-CoV-2 reported markedly different COVID-19 mortality calculated as the numbers of death per million population. Germany and United States manifested similar levels of preexisting T cell reactivity against SARS-CoV-2: 34% and 36%, respectively. However, the reported COVID-19 mortality was 114 death per million in Germany and 627 death per million in United States. Similarly, Netherlands and Sweden manifested similar levels of preexisting T cell reactivity against SARS-CoV-2: 20% and 18%, respectively. However, the reported COVID-19 mortality was 374 death per million in Netherlands and 576 death per million in Sweden. Thus, countries with similar levels of preexisting SARS-CoV-2 reactive T cells manifest different COVID-19 mortality normalized per million population. Significantly, in both instances countries with lover COVID-19 mortality are known to adhere to more strict and consistent modes of implementations of social measures designed to limit the transmission of SARS-CoV-2 (lockdown; physical distancing; mask wearing) compared to their counterparts.
In contrast, no apparent association has been observed between the pre-existing T cell immunity against SARS-CoV-2 and numbers of COVID-19 cases in different countries. In both metrics reflecting either the mortality or prevalence of the COVID-19 pandemic, numbers reported for the United States appear notable outliers likely because systematic failures to articulate and consistently implement the national pandemic mitigation strategy designed to efficiently limit the spread of the virus. Thus, lack of the apparent association between levels of pre-existing T cell reactivity against SARS-CoV-2 coronavirus in uninfected individuals and the prevalence of the COVID-19 pandemic in different countries was observed. Prevalence of the pandemic was calculated as numbers of the reported COVID-19 cases normalized per million population.
Present observations indicate that preexisting T cells cross-reactive against SARS-CoV-2 are more likely to affect diseases severity because high pre-existing immunity appears associated with lower mortality. The significant direct impact on the innate herd immunity against COVID-19 and effect on populations’ susceptibility to the infection seems less likely because no association was observed between levels of preexisting immunity and prevalence of the infection. Therefore, the herd immunity threshold required to effectively stop the pandemic cannot be significantly reduced from 60% of a population getting infected down to as low as 10% based on an R0 of 2.5 as previously suggested (9-11). Collectively, present findings indicate that the heterologous immunity facilitated by cross-reactive T cells preexisting in uninfected individuals may be one of important contributing factors affecting the clinical course and outcomes of the COVID-19 pandemic (7, 8) and support the previously articulated rationale (3) for worldwide prospective studies precisely mapping the levels of preexisting immune cross-reactivity to the clinical course and outcomes of the pandemic.
Limitations
One of the most significant limitations of this analysis is the small sample size of all reported to date studies on the levels of pre-existing T cell immunity against the SARS-CoV-2 in different countries, which is difficult to justify as representative samples of corresponding populations. Arguably, the COVID-19 mortality rate metric (also known as the case fatality rate) could be influenced by the lack of uniformity of diagnostic tests and the apparent inconsistency of the data collection and reporting in different countries, which could make uncertain the validity of observed differences between different countries.
Methods
The primary data on levels of T cell reactivity against SARS-CoV-2 in uninfected individuals that are currently available were obtained for the following five countries: United States (1); Netherlands (2); Germany (3; 7); Singapore (4); Sweden (5). These data were supplemented with numbers of COVID-19 cases and death in corresponding countries (https://coronavirus.jhu.edu/map.html) and analyzed. Mortality rates were calculated for each country based on the statistics available on October 01, 2020 and reported as two metrics: i) percent of COVID-19 death normalized to number of COVID-19 cases (also known as the case fatality rate); ii) number of COVID-19 death per one million population.
References
1. Grifoni A, Weiskopf D, Ramirez SI, etal. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell 2020; 181:1489-1501.e15.
2. Weiskopf D, Schmitz KS, Raadsen MP, Grifoni A, Okba NMA, Endeman H, et al. Phenotype of SARS-CoV-2-specific T-cells in COVID-19 patients with acute respiratory distress syndrome [preprint]. MedRxiv 2020. doi: 10.1101/2020.04.11.20062349.
3. Braun J, Loyal L, Frentsch M, Wendisch D, Georg P, Kurth F, et al. Presence of SARS-CoV-2 reactive T cells in COVID-19 patients and healthy donors [preprint]. MedRxiv 2020. https://www.medrxiv.org/content/10.1101/2020.04.17.20061440v1
4. Le Bert N, Tan AT, Kunasegaran K, etal. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 2020; 584:457-62. .
5. Sekine T, Perez-Potti A, Rivera-Ballesteros O, et al. Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19 [preprint]. BioRxiv. 2020. https://www.biorxiv.org/content/10.1101/2020.06.29.174888v1.abstract.
6. Doshi P. Covid-19: Do many people have pre-existing immunity? BMJ 2020. 370:m3563
http://dx.doi.org/10.1136/bmj.m3563.
7. Nelde A, et al. SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition. Nature Immunology. 2020. https://doi.org/10.1038/s41590-020-00808-x
8. Sette A, Crotty S. Pre-existing immunity to SARS-CoV-2: the knowns and unknowns. Nature Reviews Immunology. 20: 457-458.
9. Aguas R, Corder RM, King JG, Goncalves G, Ferreira MU, Gomes MGM. Herd immunity thresholds for SARS-CoV-2 estimated from unfolding epidemics [preprint]. medRxiv. 2020.https://doi.org/10.1101/2020.07.23.20160762.
10. Gomes MGM, Corder RM, King JG, Langwig KE, Souto-Maior C, Carneiro J, et al. Individual variation in susceptibility or exposure to SARS-CoV-2 lowers the herd immunity threshold [preprint]. MedRxiv. 2 May 2020. https://www.medrxiv.org/content/10.1101/2020.04.27.20081893v3.
11. Lourenco J, Pinotti F, Thompson C, Gupta S. The impact of host resistance on cumulative mortality and the threshold of herd immunity for SARS-CoV-2 [preprint]. medRxiv. 2020. https://www.medrxiv.org/content/10.1101/2020.07.15.20154294v1.
Competing interests: No competing interests
Dear Editor
May I be permitted to utter heresy?
There are, in every population, some individuals with an inborn resistance (even in the absence of maternal exposure) to at least one viral disease - SMALLPOX.
Some such persons escape clinical disease, one or more of the siblings become ill but recover, one or more die.
You have no longer the “opportunity” to see this.
In my paternal cousins it did happen. Pre-1939 War. They were not vaccinated.
The medical profession pats itself on the back, claiming it got rid of smallpox, by vaccination.
This suggests that the vaccinators managed to vaccinate everyone in the African Continent. Unbelievable.
If I am right. I suggest that Coronaviruses are equally unpredictable. Whether they mutate in to less fatal or more fatal descendants remains to be seen.
Competing interests: No competing interests
Dear Editor
Judging by the original article and subsequent well researched responses, to a non-scientist it tells me that the jury is out on all these discussions. In fact we haven’t even decided what jury or jurisdiction and who the judges will be once dust settles on this pandemic. The immune response to COVID-19 if and when mounted is still unknown, and what re-infection and upcoming vaccines will do to enhance still seems light years away.
Individuals' responses to infections and vaccinations have been varied, and some may often provide life long immunity whilst others need regular boosters. Along with that, knowledge of ADE (antibody derived enhancement (1) may play a role in te cytokine response in elderly people and people with significant co-morbidities. Could it be that people over a certain age group were exposed to some infections with ADE response during their lifetimes which younger generations have not seen either because of the current vaccination schedule or because that particular pathogen is not circulating currently? We need greater collaboration between clinicians, immunologists, scientists and public health professionals to mount a collective response rather than the isolationist approach seen in many areas.
Ref
1 Immune life history, vaccination, and the dynamics of SARS-CoV-2 over the next 5 years.
BY CHADI M. SAAD-ROY, CAROLINE E. WAGNER, RACHEL E. BAKER, SINEAD E. MORRIS, JEREMY FARRAR, ANDREA L. GRAHAM, SIMON A. LEVIN, MICHAEL J. MINA, C. JESSICA E. METCALF, BRYAN T. GRENFELL
PUBLISHED ONLINE 21 SEP 2020
DOI: 10.1126/science.abd7343
Competing interests: No competing interests
Dear Editor,
Should we continue with anti-covid-19 suppression measures based on a transmission model which ignored pre-existing human immunity?
We have argued from the very beginning of the pandemic that our governments based their decisions almost uniformly – with the exception of Sweden – on the advice of a far too limited group of experts, mainly a few prominent virologists and influential infectious disease modellers, well known from previous activities in pandemic planning, e.g. swine-flu, avian flu, Spanish flu. These virologists and modellers argued that SARS-CoV-2 was a completely new virus, highly contagious and deadly to everybody in the population. Accordingly, based on earlier transmission models to support pandemic influenza planning, they calculated that an uncontrolled SARS-CoV-2 epidemic would infect about 81% of the UK and the US population. Assuming an infection fatality rate (IFR) of 0.9%, they predicted 510,000 (UK) and 2.2 million (US) deaths respectively, and a worldwide death toll of 40 million. [1] Thereby, they convinced almost all governments to engage in rigid suppression strategies of non-pharmacological interventions (NPIs) to be maintained until a vaccine becomes available. [2]
As Peter Doshi describes in his excellent feature (see Box 1) [3], pre-existing immunity was also not considered in the earlier models on the swine-flu pandemic, predicting 30 million deaths worldwide from a new strain of the A/H1N1 virus, for which most people were thought to have no immunity. However, a CDC study conducted during the 2009 outbreak reported that 33% of people over 60 had cross reactive antibodies to the 2009 H1N1 strain. Hardly any people above age 60 were afflicted with swine-flu in 2009/2010 and in Germany the death toll of confirmed cases amounted to 258. [4]
Looking at official mortality statistics of the first seven months of 2020 we see differences in the pattern of mortality occurrence between countries with some short term peaks of excess mortality especially in very old people, however total mortality peaks levelled off quickly and overall the predicted magnitude of excess mortality did not occur. In Germany total mortality showed no excess during the first seven months of 2020 compared to the average of the respective time period of 2016-2019. [5] For comparison, in Belgium another country with strict lockdown measures, the population based death toll from covid-19 is 8 times higher than in Germany. Sweden, a country following a mitigation strategy without lockdown, reveals only 65% of the per capita corona deaths of Belgium. In our opinion, these real world data clearly show that the modelled projections of the severity of covid-19 infection as well as the impact of the suppression strategy do not hold. It is therefore time to question the validity of the pandemic preparedness plan including the maintenance of adaptive triggering of suppression strategies, implying that in the moment of lifting suppression measures, severe infections and deaths will occur, because herd immunity is far from being reached.
As Peter Doshi shows, herd immunity threshold (HIT) calculations have also been too simplistic, because immunity is not randomly distributed in populations, and social conditions play an important role for the response of the immune system. Instead of the often cited required HIT of 60%, the observed course of SARS-CoV-2 suggests a much lower HIT, due to pre-existing immunity such as innate immunity, cellular immunity and the occurrence of specific as well as cross-reactive antibodies.
Instead of continuing uninformative mass PCR testing, what we need are thoroughly conducted population based epidemiological studies of immunity (pre-existing, acquired, maintained) because it has been shown, that “infection with coronaviruses induces multi-specific and long-lasting T-cell immunity that affects the susceptibility to and pathogenesis of SARS-CoV-2 infection in the population”. [6] This knowledge is crucial also with respect to the usefulness and safety of covid-19 vaccines.
The suppression strategy does not appear to have protected the most vulnerable and in our eyes may have done more harm than good and should therefore be abandoned as soon as possible. As most coronavirus deaths occurred in large nursing homes and care homes, it is of paramount importance that pandemic preparedness plans pay much more attention to social and health care systems.
References
[1] Report 9: Impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand. Imperial College COVID-19 Response Team. https://doi.org/10.25561/77482
[2] Explaining the homogeneous diffusion of COVID-19 non-pharmaceutical interventions across heterogeneous countries. Sebhatu A. et al. PNAS 2020; 117 (35):21201-21208
[3] Covid-19: Do many people have pre-existing immunity? Doshi P. BMJ 2020; 370:m3563 http:// dx.doi.org/10.1136/bmj.m3563
[4] Arbeitsgemeinschaft Influenza: http:// influenza.RKI.de/saisonberichte aspx, accessed 23 Jan 2010
[5] Statistisches Bundesamt, Wiesbaden.https://www.destatis.de/DE/Themen/Gesellschaft-Umwelt/Bevoelkerung/Sterb..., accessed August 28,2020
[6] SARS-CoV-2 specific T-cell immunity in cases COVID-19 and SARS, and in infected controls. Le Bert N. et al. Nature Vol 584, 20 August 2020. https://doi.org/10.1038/s41586-020-2550-z
Competing interests: No competing interests
Dear Editor
Ref: Why is there no interest in generic approaches to promoting immunity by Sarah Lynette Stewart-Brown on 21 Sept
I would like, as a medical doctor/psychiatrist, to endorse the wise rapid medical response submitted by Sarah Lynette Stewart-Brownon stress and immunity on 21 Sept.
No doubt most of the measures imposed by the government on all of us, like frequent social isolation, financial worry and loss of freedom, can create more stress and lower the immune defence system, which will make us more susceptible to having more infections and more deaths while at the same time we are not taking any measure to strengthen our immune defence system.
It is useful to remind ourselves first of the importance of establishing well the natural immune defence system, especially in the first two years of life while breastfeeding.
So, develop natural immunisation but without introducing a lot of harmful toxic chemicals, animal and human proteins, unhygienic substances, viruses, etc, during this sensitive delicate stage of the first two years to allow the proper development of the natural immune defence system for life!
Unfortunately, it looks that this process of forming and developing the natural immune defence system may be interfered with by "pushing 12 vaccines" in these early two years of life in the small bodies of our innocent children.
It is highly recommended, I suggest, to review this procedure of giving 12 vaccines early in the life of our tiny children, especially as we today have more than 80 auto-immune diseases and many children/adults have a weak immune defence system and a lot of infections.
I humbly suggest to all medics to revisit and study well the natural defence system and its fascinating armies and its effective organs and special cells which do deal successfully with all types of viruses and bacteria by stopping them in many different interesting effective ways. Most of us do seem to have forgotten about its major role against most viruses and bacteria!
The issue of prevenion or preventing a pandemic is an excellent suggested idea and is missing today.
Apart from having first a strong natural immune defence system, one can prevent a lot of different infections, including Coronavirus, by adopting repeated daily hygienic measures and washing, especially the washing of the hands mouth nose face/eyes...
I have explained these repeated daily hygienic measures which I did suggest to the British Muslim Community in my rapid response:
Islamic Instructions to Avoid Coronavirus/Covid-19 among British Muslims
https://www.bmj.com/content/369/bmj.m1932/rr-26
All these Islamic hygienic measures are normally done in WUDU/ABLUTION before the 5 daily prayers called SALAT, which are supposed to relieve us from stress and worry and boost our immunity too..
DR MAJID KATME (MBBCh, DPM)
Retired psychiatrist
Competing interests: No competing interests
Dear Editor,
Prof Sarah Stewart-Brown asks why nobody talks about varieties of immunity produced by means not likely to produce cash.
She has given the answer herself.
Very rich men and women have poured their millions (or billions) into charities promoting vaccination. Example: the Gates.
Competing interests: No competing interests
Dear Editor
Among the many important issues being aired about immunity to covid-19 in this and other articles in this issue, some are receiving scant attention. A long series of trials inoculating individuals with a range of viruses, including coronaviruses, and investigating who developed symptoms and became ill, consistently showed increased risk for those who were stressed.[1] These trials also showed that social connectedness protected against infection.[2] The findings have been corroborated in other studies.[3,4] The greater level of risk from covid-19 among populations at high risk for stress - those with low incomes and minority ethnic groups - are entirely in keeping with the possibility that stress and social isolation play a role in immunity to this virus.
The solutions of lockdown, social distancing and quarantine have created very great stress for a significant proportion of the population and an unprecedented level of social isolation for those most at risk, so it is perhaps not surprising that appetite for considering the possibility that preventive measures may have contributed to the pandemic is low.
Research into human wellbeing has prompted research into factors that prevent stress.[5] Those that are recognised are lifestyles currently promoted for other reasons (physical activity, healthy diets, exposure to green spaces) and activities that enhance social connectedness. Other candidates with enough evidence to be considered seriously include mindfulness, Tai Chi, Yoga, singing, massage and other body work.[6-9] There is reasonable evidence and plausible biological mechanisms to show that these activities enhance immunity and create resilience to viral infection. The immune system is very complex,[10] and studies usually measure only one aspect of immunity. Showing that an activity enhances levels of IGA, for example, does not provide cast iron evidence that it could be useful in preventing a pandemic, but it has to be worth investigating in the current climate. Small reductions in risk across large sections of the population like wearing face masks are useful additions to pandemic control. Instead, face to face, hands-on and group-based stress preventing activities, as well as positive social contact were shut down during lockdown and have been restricted again in attempts to prevent a second wave.
So why are there no urgent calls to find out whether these very low cost, popular wellbeing enhancing activities with no damaging economic consequences, boost immunity, in what way and by how much? If promoting these activities could offer a measure of protection against this and the next pandemic policy making could be directed towards promoting rather than restricting them. It is hard not to wonder if the low potential for making money from these activities and the high level of discomfort felt by many in the medical profession about possible mind-body links and the benefits of integrative health care approaches are playing a part in preventing serious interest and investment in research.
1. Cohen S. The Pittsburgh common cold studies: psychological predictors of susceptibility to respiratory infections illness Int. J. Behav. Medicine 2005;12:123-131
2. Hasselmo K., Mehl MR, Tackman AM., Carey AL, Wertheimer AM, Stowe RP, Sbarra DA. Objectively Measured Social Integration Is Associated With an Immune Risk Phenotype Following Marital Separation Annals of Behavioral Medicine 2018;52:130–145
3. Coe CL, Laudenslager ML, Psychosocial influences on immunity, including effects on immune maturation and senescence. Brain Behav Immun 2007;21:1000-1008
4. Morey JN, Boggero IA, Scott AB, Segerstrom SC. Current Directions in Stress and Human Immune Function. Curr Opin Psychol. 2015;5:13-17. doi:10.1016/j.copsyc.2015.03.007
5. https://whatworkswellbeing.org/
6. R. J. Beck, T. C. Cesario, A. Yousefi and H. Enamoto Choral Singing, Performance Perception, and Immune System Changes in Salivary Immunoglobulin A and Cortisol Music Perception: An Interdisciplinary Journal 2000;18:87-106
7. Jing Liu, Peijie Chen, Ru Wang, Yonghong Yuan, and Chunying Li. Effect of Tai Chi Exercise on Immune Function in Middle-aged and Elderly Women. J Sports Med Doping Stud 2012, 2:6http://dx.doi.org/10.4172/2161-0673.1000119.
8. Gopal A, Mondal S, Gandhi A, Arora S, Bhattacharjee J. Effect of integrated yoga practices on immune responses in examination stress - A preliminary study. Int J Yoga. 2011;4(1):26-32. doi:10.4103/0973-6131.78178
9. Major B, Rattazzi L, Brod S, et al. Massage-like stroking boosts the immune system in mice. Sci Rep 2015; 5:10913
10. Mahase E. Covid-19: Where are we on immunity and vaccines? BMJ 2020;370:m3096
Competing interests: No competing interests
Dear Editor,
Thank you to Dr Doshi for raising the profile of T-cells. Incidentally, German researchers found that a staggering 81% of individuals had pre-existing T-cells that cross-react with SARS-CoV-2 epitopes [1]. This fits with modelling in May by Imperial College’s Professor Friston, a world authority in mathematical modelling of complex dynamic biological systems, indicating that around 80% and 50% of the German and UK populations, respectively, are resistant to COVID-19: https://unherd.com/2020/06/karl-friston-up-to-80-not-even-susceptible-to...
Antibodies can only latch onto and help destroy pathogens outside cells and may also occasionally, paradoxically, enhance a pathogen’s ability to infect cell instead by antibody dependent ”enhancement” or ADE. It is only the T-cell that can cleverly sense and destroy pathogens inside infected cells using “sensors” which detect foreign protein fragments.
In the late 60’s the Lancet described a case of a child with agammaglobulinemia, a condition in which absence of B cells prevent them from producing antibodies, who overcame a measles infection quite normally and did not become re-infected thereafter. We now know that, although this condition can compromise immunity, in that particular case the rest of the immune functions, including T-cells, must have been perfectly up to the job of clearing infection and establishing immune memory without help from antibodies. The importance of T-cells in fighting SARS-CoV-1 and establishing immune memory has also been well documented and discussed in a number of pre-COVID papers from 2017 and earlier [2].
Then, early in April, it was reported that two patients with agammaglobulinemia overcame COVID-19 infections without requiring ventilation [3], prompting the Italian authors to write: “This observation suggests that T‐cell response is probably important for immune protection against the virus, while B‐cell response might be unessential”.
All this should have shifted the focus of efforts towards T-cells at an early stage - the real question is why mainstream media and others continued to focus efforts and narrative on antibodies. Is it because vaccines are good at provoking antibody responses but not so great at generating T-cells? Some of the vaccines presently under trial do elicit some T-cells but it seems that neither the quantity nor variety are hugely impressive.
Does this matter? Apparently so: Research establishments including Yale found that in mild or asymptomatic cases, many T-cells are produced. These were highly varied, responding not just to parts of the Spike, S protein or Receptor Binding Domain but to many other parts of the virus [1, 4-6]. Notably, in these mild cases there were few or no detectable antibodies. Conversely, the severely ill produced few T-cells with less variety but had plenty of antibodies. What is also of interest is that men produced fewer T-cells than women, and unlike women, their T-cell response reduced with age [7].
So why are some people unable to mount a good protective T-cell response? The key to this question might be a 10-year-old Danish study led by Carsten Geisler, head of the Department of International Health, Immunology and Microbiology at the University of Copenhagen [8]. Geisler noted that "When a T cell is exposed to a foreign pathogen, it extends a signalling device or 'antenna' known as a vitamin D receptor, with which it searches for vitamin D,", and if there is an inadequate vitamin D level, "they won't even begin to mobilize." In other words, adequate vitamin D is critically important for the activation of T-cells from their inactive naïve state. The question of whether T-cells might also need a continuing supply of vitamin D to prevent the T-cell exhaustion and apoptosis observed in some serious COVID-19 cases [9] deserves further research.
High levels of vitamin D are also critical for first line immune defences including physical mucosal defences, human antiviral production, modulating cytokines, reducing blood clotting and a whole host of other important immune system functions [10]. The obese, diabetics and people of BAME origin are far more deficient in vitamin D and men have lower levels than women [10].
Another intriguing clue is that Japan has the highest proportion of elderly on the planet but despite lack of lockdowns, little mask wearing and high population densities in cities, it escaped with few COVID deaths. Could this, at least in part, be because of extraordinarily high vitamin D levels of over 30 ng/ml in 95% of the active elderly [11]? By comparison, UK average levels are below 20ng/ml [10]. Vitamin D is made in the skin from the action of UV sunlight, food usually being a poor source, but the Japanese diet includes unusually high levels. Sunny countries near the equator (e.g. Nigeria, Singapore, Sri Lanka) also have very low COVID related deaths.
The results of the first vitamin D intervention double blind RCT for COVID was published on 29 August by researchers in Córdoba, Spain. This very well conducted study produced spectacular outcomes for the vitamin D group (n=50), virtually eliminating the need for ICU (reducing it by 96%) and eliminating deaths (8% in the n=26 control group). Although this was a small trial, the ICU results are so dramatic that they are statistically highly significant [12].
Substantially more vitamin D is required for optimal immune function than for bone health. It seems Dr Fauci is not ignorant of this, having apparently confirmed on TV and by email that he takes 6,000 IU daily! (see Dr John Campbell on YouTube Vitamin D and pandemic science, 16 September 2020). Meanwhile the US’s health body continues to recommend only 600-800 IU and the UK’s, only 400 IU.
It is high time for joined up solid scientific rationale to overthrow mainstream narratives based on an alternative “science” controlled by industry interests/politics. Beda M Stadler, the former Director of the Institute for Immunology at the University of Bern, a biologist and Professor Emeritus, certainly appears to think so (see Ivor Cummins Ep91 Emeritus Professor of Immunology...Reveals Crucial Viral Immunity Reality on YouTube, 28 July 2020).
In the same way that prior infections protect us against future infections by means of cross-reacting T-cells, overcoming COVID-19 naturally offers potential for greater protection against future coronaviruses. Vaccines have their place but so do our amazingly complex, sophisticated, highly effective immune systems which have evolved over millennia to protect us from a world teeming with trillions of pathogens.
References
1. Annika Nelde, Tatjana Bilich, Jonas S. Heitmann et al. SARS-CoV-2 T-cell epitopes define heterologous and COVID-19-induced T-cell recognition, 16 June 2020, Research Square https://www.researchsquare.com/article/rs-35331/v1%20
2. William J.Liuabc et al. T-cell immunity of SARS-CoV: Implications for vaccine development against MERS-CoV.Antiviral Research. Volume 137, January 2017, Pages 82-92 https://doi.org/10.1016/j.antiviral.2016.11.006
3. Soresina, A, Moratto, D, Chiarini, M, et al. Two X‐linked agammaglobulinemia patients develop pneumonia as COVID‐19 manifestation but recover. Pediatr Allergy Immunol. 2020; 31: 565– 569. https://doi.org/10.1111/pai.13263
4. Avraham Unterman, et al. Single-Cell Omics Reveals Dyssynchrony of the Innate and Adaptive Immune System in Progressive COVID-19. medRxiv 2020.07.16.20153437; doi: https://doi.org/10.1101/2020.07.16.20153437
5. Leticia Kuri-Cervantes, et al. Immunologic perturbations in severe COVID-19/SARS-CoV-2 infection. bioRxiv 2020.05.18.101717; doi: https://doi.org/10.1101/2020.05.18.101717
6. Floriane Gallais, Aurelie Velay, Marie-Josee Wendling, Charlotte Nazon, Marialuisa Partisani, Jean Sibilia, Sophie Candon, Samira Fafi-Kremer. Intrafamilial Exposure to SARS-CoV-2 Induces Cellular Immune Response without Seroconversion. medRxiv 2020.06.21.20132449; doi: https://doi.org/10.1101/2020.06.21.20132449
7. Takahashi T, Wong P, Ellingson M, et al. Sex differences in immune responses to SARS-CoV-2 that underlie disease outcomes. Preprint. medRxiv. 2020;2020.06.06.20123414. Published 2020 Jun 9. doi:10.1101/2020.06.06.20123414
8. Von Essen MR, Kongsbak M, Schjerling P, Olgaard K, Odum N, Geisler C. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol. 2010;11(4):344-349. doi:10.1038/ni.1851
9. Diao B, Wang C, Tan Y, et al. Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19). Front Immunol. 2020;11:827. Published 2020 May 1. doi:10.3389/fimmu.2020.00827
10. King, E.. The Role of Vitamin D deficiency in COVID-19 related deaths in BAME, Obese and Other High-risk Categories. 2020, June 17. https://doi.org/10.31232/osf.io/73whx
11. Nakamura K. Vitamin D insufficiency in Japanese populations: from the viewpoint of the prevention of osteoporosis. J Bone Miner Metab. 2006;24(1):1-6. doi:10.1007/s00774-005-0637-0
12. Marta Entrenas Castillo et al. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. The Journal of Steroid Biochemistry and Molecular Biology. Volume 203, October 2020, 105751. https://doi.org/10.1016/j.jsbmb.2020.105751
Competing interests: No competing interests
Re: Covid-19: Do many people have pre-existing immunity?
Dear Editor,
As mentioned in the article, we're seeing studies on frozen, donor blood from prior to SARS-CoV-2 being identified showing immune responses to the disease. Here are two more that may indicate a "0th" wave starting in September 2019 or earlier. Much of the speculation concerning the prevalance of immunity without symptomatic disease may be explained by a possible "0th" wave prior to awareness of the disease being widespread. This would also call into question Wuhan being the epicenter.
The first article showing >1% of donor blood in nine US states with antibodies: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1785/60... Second article showing 14% with antibodies in Italy in Sept. 2019 and 16% in Oct. 2019: https://journals.sagepub.com/doi/full/10.1177/0300891620974755
Since antibody responses to SARS-CoV-2 are observed to be somewhat ephemeral, lasting on the order of a few months, it would seem that the blood donors would have to have been infected by and recovered from SARS-CoV-2 within the time window when antibodies are present. The donors would have to have recovered from a symptomatic or asymptomatic infection which would likely mean a time lag between the infection and the donation.
It may be possible to retroactively obtain consent from donors to allow their blood to be used in longitudinal studies. Since we now know that T cell reactivity is a significant factor, future frozen blood studies should also look at T cell reactivity, especially since T cell reactivity lasts longer than antibody immunity.
The conventional hypothesis is: The disease got to the US in late January 2020. We can't explain why children and many adults appear to be immune.
Another hypothesis that satisfies Occam's Razor is: As may be demonstrated by the articles above, there was a 0th wave from September 2019 or earlier until the disease was officially recognized. It may have gone through the schools like epidemics often do, confering immunity to many children. Many adults may also have been infected in the 0th wave, and are also immune. By the time antibody testing became widespread most 0th wave victims had ceased to have antibodies.
John Lewicke (Mason, NH, US)
Competing interests: No competing interests