Protection against SARS-CoV-2 after Vaccination and Previous Infection

To the Editor

In previously uninfected participants in the SARS-CoV-2 Immunity and Reinfection Evaluation (SIREN) study, Hall et al. (March 31 issue)1 report reduced protection from SARS-CoV-2 infection after 6 months following the receipt of two vaccine doses. Among unvaccinated participants, those with natural infection-acquired immunity had an 81 to 89% lower risk of infection for up to 1 year after infection than those who were previously uninfected. Infection-acquired immunity then waned in unvaccinated participants, but protection remained higher than 90% in subsequently vaccinated persons.

The authors note that sustained infection-acquired protection in their cohort was possibly affected by repeated occupational exposure to Covid-19. However, one mechanism of potentially paramount importance in explaining their finding of greater protection associated with infection-acquired immunity alone than with vaccine-acquired immunity alone is missing from their discussion: the distinct immunization routes followed by natural infection (airway mucosal route) as compared with intramuscular vaccination (systemic route). There is now evidence that critical components of the mucosal immunity network play a key role in fighting SARS-CoV-2 infection,2-5 including secretory immunoglobulin A and tissue-resident memory cells (elements of local adaptive immunity) and mucosa-associated invariant T cells, mucosal complement activation, and mucosal interferons (elements of local innate immunity).

Claude Matuchansky, M.D.
Paris Diderot University, Paris, France

No potential conflict of interest relevant to this letter was reported.

This letter was published on June 15, 2022, at

  1. 1. Hall V, Foulkes S, Insalata F, et al. Protection against SARS-CoV-2 after Covid-19 vaccination and previous infection. N Engl J Med 2022;386:1207-1220.

  2. 2. Russell MW, Moldoveanu Z, Ogra PL, Mestecky J. Mucosal immunity in COVID-19: a neglected but critical aspect of SARS-CoV-2 infection. Front Immunol 2020;11:611337-611337.

  3. 3. Matuchansky C. Mucosal immunity to SARS-CoV-2: a clinically relevant key to deciphering natural and vaccine-induced defences. Clin Microbiol Infect 2021;27:1724-1726.

  4. 4. Wang Z, Lorenzi JCC, Muecksch F, et al. Enhanced SARS-CoV-2 neutralization by dimeric IgA. Sci Transl Med 2021;13(577):eabf1555-eabf1555.

  5. 5. Farber DL. Tissues, not blood, are where immune cells function. Nature 2021;593:506-509.


The authors and a colleague reply: We agree with Matuchansky that mucosal immunity is an important area for further study, particularly in investigating the differences between infection-acquired and vaccine-acquired protection against SARS-CoV-2 infection. We are examining this in a nested cohort of participants in the SIREN study who are coenrolled in the PITCH (Protective Immunity from T Cells in Healthcare Workers) Study,1 which investigates cellular immune responses and mucosal immunity.

Susan Hopkins, F.R.C.P.
Victoria Hall, F.F.P.H.
U.K. Health Security Agency, London, United Kingdom

Paul Klenerman, F.Med.Sci.
University of Oxford, Oxford, United Kingdom

Dr. Klenerman reports no potential conflict of interest relevant to this letter. Since publication of their article, the authors report no further potential conflict of interest.

This letter was published on June 15, 2022, at

  1. 1. Payne RP, Longet S, Austin JA, et al. Immunogenicity of standard and extended dosing intervals of BNT162b2 mRNA vaccine. Cell 2022;184:5699-5714.

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