Risk of BA.5 infection in people exposed to previous variants of SARS-CoV-2

For the editor:

In recent months, omicron (B.1.1.529) has emerged as the dominant variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), displaying 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 escape from the immunity induced by BA.1 and BA.2.2.3 The protection offered by BA.1 against infection with the BA.5 subvariant is essential because suitable vaccines in clinical trials are based on BA.1.

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

Protective effect of prior SARS-CoV-2 infection on Omicron BA.5 subvariant infection.

As shown in panel A, we identified time periods (in different colors) where a variant was represented in >90% of sample isolates (national severe acute respiratory syndrome coronavirus 2 data [SARS-CoV-2] genetic diversity monitoring4). Periods in gray 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 grouped BA.1 and BA.2 together in the analysis. We did not include anyone infected within 90 days prior to omicron BA.5 subvariant dominance. Panel B shows the efficacy of protection against infection during the BA.5 dominance period (from June 1, 2022) in people with infection in the dominance periods of different variants, as depicted in panel A, compared to people without any documented infections through June 1. People who had two infections before June 1 were not included in the study. The bars 𝙸 represent the 95% confidence intervals.

National genetic surveillance of SARS-CoV-2 identified periods when different variants accounted for more than 90% of isolates.4 We identified all the people who had a first infection in the periods of dominance of each variant, to calculate their risk of infection during the period of BA dominance.5 (Figure 1A). We grouped BA.1 and BA.2 together because of 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 was protective against BA.5 infection (Figure 1B and the table S1 in the Additional appendix, available with the full text of this letter at NEJM.org), and this protection was maximal for prior BA.1 or BA.2 infection. These data should be seen in the context of breakthrough infections in a highly vaccinated population, given that in Portugal more than 98% of the study population completed the primary vaccination by 2022.

The study design cannot eliminate all confounding factors (see Discussion section in the Additional appendix). Additionally, a limitation is the putative effect of immune decline in a population with hybrid immunity (prior infection and vaccination). We found that infection with BA.1 or BA.2 in vaccinated individuals provided higher protection against BA.5 than infection with pre-omicron variants, consistent with a recent report with a negative test design .5 However, BA.1 or BA.2 infections occurred closer to the period of BA.5 dominance than infections with earlier variants. The protection afforded by prior BA.1 or BA.2 infection is thought to be very low, given the high number of BA.5 infections among people with prior BA.1 or BA.2 infection. BA.2. Our data indicate that this perception is likely a consequence of more people being infected with BA.1 or BA.2 than with infection with 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 people with a history of SARS-CoV-2 infection in a highly vaccinated population, especially for infections prior to BA.1 or BA.2, than in uninfected persons.

João Malato, M.Sc.
João Lobo Antunes Molecular Medicine Institute, Lisbon, Portugal

Ruy M. Ribeiro, D.Phil.
Los Alamos National Laboratory, Los Alamos, New Mexico

Peter P. Leite, MD
Pedro Casaca, MD
Eugenia Fernandes, Ph.D.
General Directorate of Health, Lisbon, Portugal

Carlos Antunes, Ph.D.
University of Lisbon, Lisbon, Portugal

Valter R. Fonseca, MD, Ph.D.
General Directorate of Health, Lisbon, Portugal

Manuel C. Gomes, Ph.D.
University of Lisbon, Lisbon, Portugal

Luis Graca, MD, D.Phil.
João Lobo Antunes Molecular Medicine Institute, Lisbon, Portugal

Supported by the European Union Horizon 2020 research and innovation program (ERA project number, 952377–iSTARS) and by foundation for science and technology by 081_596653860 and PTDC/MAT-APL/31602/2017 and by National Institutes of Health grant R01-AI116868.

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

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

Drs. Gomes and Graça also contributed to this letter.

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

  2. 2. YuJ, IS Necklace, Rowe M, et al. Neutralization of SARS-CoV-2 omicron BA.1 and BA.2 variants. N English J med 2022;386:15791580.

  3. 3. Cao Y, This is Simai A, Jian F, et al. BA.2.12.1, BA.4 and BA.5 evade antibodies caused by omicron infection. Nature 2022;608:593602.

  4. 4. National Institute of Health Dr. 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 HN, Chemaitelly H, Ayoub HH, et al. Protection of natural SARS-CoV-2 infection against reinfection with omicron BA.4 or BA.5 subvariants. July 12, 2022 (https://www.medrxiv.org/content/10.1101/2022.07.11.22277448v1). preprint.

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