Risk of BA.5 infection in individuals exposed to prior SARS-CoV-2 variants

To the editors:

In recent months, omicron (B.1.1.529) became the dominant variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some degree of immune evasion.1 The initial omicron subvariants, BA.1 and BA.2, are gradually being replaced by BA.5 in many countries, possibly due to greater transmissibility and partial evasion of BA.1- and BA.2-induced immunity.2.3 The protection offered by BA.1 against infection by the BA.5 subvariant is critical because modified vaccines under clinical trials are based on BA.1.

Portugal was one of the first countries to be hit by a BA.5 dominance. We used the 2019 National Registry for Coronavirus Disease 2019 (Covid-19) (SINAVE) to calculate the risk of BA.5 infection in individuals with documented infection with previous variants, including BA.1 and BA.2. The registry includes all reported cases in the country, regardless of clinical presentation.

Protective effect of previous SARS-CoV-2 infection on infection with the Omicron BA.5 subvariant.

As shown in Panel A, we identified the periods (in different colors) in which one variant was represented in more than 90% of the sample isolates (data from the national severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] genetic diversity surveillance4). The gray periods represent times when more than one variant was in circulation. Given the relatively slow transition between dominance by the omicron BA.1 subvariant and dominance by the omicron BA.2 subvariant, we pooled BA.1 and BA.2 in the analysis. We did not include anyone infected in the 90 days before dominance by the omicron BA.5 subvariant. Panel B shows the efficacy of protection against infection during the period of BA.5 dominance (as of June 1, 2022) in individuals with one infection in the periods of dominance of different variants, as shown in Panel A, compared to individuals without only documented infection until June 1. Individuals with two infections prior to June 1 were not included in the study. ūĚôł bars represent 95% confidence intervals.

The national SARS-CoV-2 genetic surveillance identified periods when different variants represented more than 90% of the isolates.4 We identified all individuals who had a first infection in periods of dominance of each variant, to calculate their infection risk during the period of BA.5 dominance (Figure 1A). We pooled BA.1 and BA.2 due to the slow transition between the two subvariants in the population. Finally, we calculated the risk of BA.5 infection for the population that had no documented infection before BA.5 dominance (June 1, 2022).

We found that prior SARS-CoV-2 infection had a protective effect against BA.5 infection (Figure 1B and Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org), and this protection was maximal for prior infection with BA.1 or BA.2. These data should be considered in the context of breakthrough infections in a highly vaccinated population, as in Portugal more than 98% of the study population completed the primary vaccination course before 2022.

The study design cannot eliminate all confounders (see the Discussion section in the supplementary appendix). In addition, a limitation is the putative effect of immune system decline in a population with hybrid immunity (prior infection and vaccination). We found that BA.1 or BA.2 infection in vaccinated subjects offered higher protection against BA.5 than infection with pre-omicron variants, in agreement with a recent report with a test-negative design.5 However, BA.1 or BA.2 infections occurred closer to the period of BA.5 dominance than infections with earlier variants. There is a perception that the protection afforded by a prior BA.1 or BA.2 infection is very low, given the high rate of BA.5 infections in individuals with a prior BA.1 or BA.2 infection . Our data indicate that this perception is likely due to the larger group of individuals with BA.1 or BA.2 infection than with infection by other subvariants, and it is not supported by the data.

Overall, we found that breakthrough infections with the BA.5 subvariant were less likely in individuals with a prior SARS-CoV-2 infection history in a highly vaccinated population, especially for prior BA.1 or BA.2 infection, than in uninfected individuals.

Joao Malato, M.Sc.
Instituto de Medicina Molecular Jo√£o Lobo Antunes, Lisbon, Portugal

Ruy M. Ribeiro, D. Phil.
Los Alamos National Laboratory, Los Alamos, NM

Pedro P. Leite, MD
Pedro Casaca, Maryland
Eugenia Fernandes, Ph.D.
Direc√£o Geral da Saude, Lisbon, Portugal

Carlos Antunes, Ph.D.
Universidade de Lisboa, Lisbon, Portugal

Valter R. Fonseca, MD, Ph.D.
Direc√£o Geral da Saude, Lisbon, Portugal

Manuel C. Gomes, Ph.D.
Universidade de Lisboa, Lisbon, Portugal

Luis Graca, MD, D. Phil.
Instituto de Medicina Molecular Jo√£o Lobo Antunes, Lisbon, Portugal
[email protected]

Supported by the European Union Horizon 2020 research and innovation program (ERA project number, 952377‚ÄďiSTARS) and by Funda√ß√£o para a Ci√™ncia ea Tecnologia up to and including 081_596653860 and PTDC/MAT-APL/31602/2017 and up to National Health Institutes grant R01-AI116868.

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter was published on NEJM.org on August 31, 2022.

drs. Gomes and Graca contributed equally to this letter.

  1. 1. Qu P, Faraone J, Evans JP, et al. Neutralization of the SARS-CoV-2 omicron BA.4/5 and BA.2.12.1 subvariants. N Engl J Med 2022;386:25262528.

  2. 2. Yu J, necklace AY, Rowe M, et al. Neutralization of the SARS-CoV-2 omicron BA.1 and BA.2 variants. N Engl J Med 2022;386:15791580.

  3. 3. Cao Y, Yismayi A, Jian F, et al. BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by omicron infection. Nature 2022;608:593602.

  4. 4. Instituto Nacional de Saude Doutor Ricardo Jorge. Genetic diversity of the novel coronavirus SARS-CoV-2 (COVID-19) in Portugal. (in Portuguese) 2022 (https://insaflu.insa.pt/covid19).

  5. 5. Altarawneh HNO, Chemaitelly H, Ayoub HHet al. Protection of natural SARS-CoV-2 infection from reinfection with the ommicron BA.4 or BA.5 subvariants. July 12, 2022 (pre-print.

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