key: cord-0954457-wv66ehaw
authors: Garg, Pramod Kumar; Thiruvengadam, Ramachandran
title: Effectiveness of SARS-CoV-2 vaccines in the post-natural infection world
date: 2022-04-01
journal: Lancet Infect Dis
DOI: 10.1016/s1473-3099(22)00207-9
sha: 2439dded41d5631f48a9f3204df5f02e4e2d3869
doc_id: 954457
cord_uid: wv66ehaw

nan

Natural viral infections provide immunity from subsequent infection through a repertoire of memory T cells and B cells, except when the virus mutates to an extent that it evades recognition by memory cells. 1 Vaccines are designed to represent the virus either in the form of an inactivated or attenuated whole virus or an immunogenic subunit such as the spike protein in the case of SARS-CoV-2. 2 After a natural infection, the immune system assesses the virus in multiple ways and provides both antibody-mediated and cellular protection. 3, 4 As the SARS-CoV-2 pandemic has relentlessly progressed, with multiple waves, the immune landscape of the global population has transformed from being immune naive to having natural infection-induced immunity. Although vaccinating the naive population is logical, an important question arises of whether to vaccinate those who were previously infected with SARS-CoV-2. The need for boosting natural immunity, through vaccination, comes from the waning of immunity, with declining antibody titres, and the emergence of SARS-CoV-2 variants with immune-evasion properties.

In The Lancet Infectious Diseases, Thiago Cerqueira-Silva and colleagues have addressed the issue of vaccine effectiveness among individuals who were previously infected. 5 For this study, the authors used national COVID-19 notification, hospitalisation, and vaccination datasets from Brazil to assess effectiveness against symptomatic infection, hospitalisation, and death for the four vaccines in use in the country during the study period: CoronaVac (Sinovac), ChAdOx1 nCoV-19 (Oxford-AstraZeneca), Ad26.COV2.S (Janssen), and BNT162b2 (Pfizer-BioNtech). Of the people who had previous confirmed SARS-CoV-2 infection, the authors included 22 566 symptomatic individuals with RT-PCRpositive reinfection and 145 055 negative RT-PCR tests from 68 426 symptomatic matched controls in a test-negative case-control study. After adjusting for important confounders, vaccine effectiveness against symptomatic infection 14 days or more from complete vaccination after a previous natural infection was 39·4% (95% CI 36·1-42·6) for CoronaVac, 56·0% (51·4-60·2) for ChAdOx1 nCoV-19, 44·0% (31·5-54·2) for Ad26. COV2.S (single-dose vaccine), and 64·8% (54·9-72·4) for BNT162b2. Vaccine effectiveness against hospitalisation or death after complete vaccination was more impressive: 81·3% (75·3-85·8) for CoronaVac, 89·9% (83·5-93·8) for ChAdOx1 nCoV-19, 57·7% (-2·6 to 82·5) for Ad26. COV2.S, and 89·7% (54·3-97·7) for BNT162b2.

The study has some major strengths. First, the linkage of three national databases for SARS-CoV-2 testing, disease surveillance for COVID-19, and immunisation. This showcases the importance of population-level data and the power of big-data analysis. Second, the comprehensive evaluation of vaccine effectiveness of four vaccines used globally. And third, the study of the dose-response relationship. However, an important missing piece of information is the SARS-CoV-2 variants against which vaccine effectiveness estimates are reported. This absence is important in view of variable vaccine effectiveness against different variants. 6 The vaccine effectiveness estimates in the study by Cerqueira-Silva and colleagues are generally lower than those in naive populations reported earlier. 6, 7 However, this discrepancy is expected given that Cerqueira-Silva and colleagues' estimates were for additional protection provided by vaccination over and above that offered by immunity resulting from natural infection. Natural infection might act as a priming or booster dose; in a previous study, 8 protection against reinfection was maintained at greater than 90% for more than 6 months after vaccination among participants with natural immunity who were subsequently vaccinated, even in those who were infected more than 12 months before vaccination. Protection as high as 82%, similar to two vaccine doses, was shown in individuals previously infected who had received a single dose of vaccine. 9 These clinical findings are corroborated by in-vitro immunological studies showing that humoral and cellular immune responses are high after the multiple antigen exposure provided by natural infection and vaccination. 10, 11 In addition to antibody-mediated immunity, cellular T-cell responses provide protection against severe disease, hospitalisation, and death. 6 The results of Cerqueira-Silva and colleagues' study and other recent studies challenge the concept of population-level herd immunity through natural infection alone against SARS-CoV-2 and suggest that vaccinating individuals who were previously infected provides further protection, particularly against severe disease. These data should help guide policy decisions and mitigate vaccine hesitancy among people who have previously had SARS-CoV-2 infection.

However, some clinical and immunological questions remain to be answered. Primary exposure to an antigen leads to epitope-specific B-cell memory known as immune imprinting. Barring the ancestral virus infection, subsequent SARS-CoV-2 infections during multiple waves caused by variants have led to heterologous exposure to virus antigens. How immune imprinting by the first exposure, either by the virus or vaccine, affects the durability and breadth of immune responses remains to be studied. What additional protection does natural infection provide to vaccinated individuals and how durable is this protection? And what is the optimal timing of vaccination after natural infection? These questions are important in view of the large swath of the global population who have been exposed to natural infections caused by delta (B.1.617.2) and omicron (B.1.1.529) variants.

Hybrid immunity due to exposure to natural infection and vaccination is likely to be the norm globally and might provide long-term protection even against emerging variants. Besides vaccination, continued surveillance for further emergence of variants for their immune evasiveness and pathogenicity should continue.

We declare no competing interests.

Translational Health Science and Technology Institute, Faridabad, NCR Delhi 121001, India

Protective immunity after recovery from SARS-CoV-2 infection

Review of COVID-19 vaccine subtypes, efficacy and geographical distributions

The T cell immune response against SARS-CoV-2

Antibody course and memory B-cell response in the first year after SARS-CoV-2 infection

Effectiveness of CoronaVac, ChAdOx1 nCoV-19, BNT162b2, and Ad26.COV2.S among individuals with previous SARS-CoV-2 infection in Brazil: a test-negative, case-control study

Effectiveness of ChAdOx1 nCoV-19 vaccine against SARS-CoV-2 infection during the delta (B.1.617.2) variant surge in India: a test-negative, case-control study and a mechanistic study of post-vaccination immune responses

Effectiveness of COVID-19 vaccines against SARS-CoV-2 infection with the delta (B.1.617.2) variant: second interim results of a living systematic review and meta-analysis

Protection against SARS-CoV-2 after COVID-19 vaccination and previous infection

Effectiveness of the BNT162b2 vaccine after recovery from COVID-19

Long-term durable humoral immune response to heterologous antigenic exposure post six months by natural SARS-CoV-2 infection and vaccination. medRxiv 2022

Heterologous infection and vaccination shapes immunity against SARS-CoV-2 variants