BA.5 infection risk in humans exposed to previous SARS-CoV-2 variants

To the editor:

In recent months, omicron (B.1.1.529) has emerged as a major variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibiting some degree of immune evasion.1 The original omicron sub-variants BA.1 and BA.2 are gradually being replaced by BA.5 in many countries, possibly due to greater transmissibility and partial escape from BA.1 and BA.2-induced immunity.2,3 The protection provided by BA.1 against infection by the BA.5 subvariant is critical because the adapted vaccine in clinical trials is based on BA.1.

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

Protection from previous SARS-CoV-2 infection against infection by an Omicron BA.5 subvariant.

As shown in panel A, we identified periods (in different colors) where a variant was present in more than 90% of the sample isolates (data from national SARS-CoV-2) [SARS-CoV-2] Genetic diversity monitoring4). Periods in grey represent times when more than one variant was in circulation. Given the relatively slow transition between the dominance of the omicron BA.1 subvariant and the dominance of the omicron BA.2 subvariant, we combined BA.1 and BA.2 in our analysis. We did not include anyone infected within the first 90 days of omicron BA.5 subvariant dominance. Panel B shows the predominance of different variants during the period of BA.5 dominance (from June 1, 2022) compared to people without any documented infection During the period there is an infection protection efficacy against infection in people until June 1st. People with two infections before June 1 were not included in the study. š™ø Bars represent 95% confidence intervals.

National SARS-CoV-2 genetic surveillance identified periods when different variants represented more than 90% of isolates.4 We identified all those who were first infected during the dominant period of each variant to calculate their risk of infection during the BA.5 dominant period (Figure 1A). We merged BA.1 and BA.2 because of the slow transition between the two subvariables in the population. Finally, we calculated the BA.5 risk of infection in the population without any documented infection prior to BA.5 dominance (June 1, 2022).

We found that previous SARS-CoV-2 infection was protective against BA.5 infection (Figure 1B and Table S1 in the Supplementary Appendix, available at with the full text of this letter), this protection was greatest against prior infection with BA.1 or BA.2. Given that in Portugal, more than 98% of the study population completed the primary vaccination series by 2022, these data should be considered in the context of breakthrough infections in the highly vaccinated population.

The study design could not eliminate all confounding factors (see the Discussion in the Supplementary Appendix). In addition, a limitation is the putative effect of immune weakening in populations with mixed immunity (previous infection and vaccination). We found that infection with BA.1 or BA.2 in vaccinated individuals conferred greater protection against BA.5 than infection with the pre-omicron variant, consistent with a recent report of a test-negative design.5 However, BA.1 or BA.2 infection occurred closer to the period of BA.5 dominance than infection of the previous variant. Given the high number of people previously infected with BA.1 or BA.2 who are infected with BA.5, it is thought that the protection afforded by previous infection with BA.1 or BA.2 is very low. Our data suggest that this perception may be the result of larger populations infected with BA.1 or BA.2 than other subvariants, and are not supported by data.

Overall, we found that in highly vaccinated populations, especially for those with previous BA.1 or BA.2 infection, those with a history of SARS-CoV-2 infection developed BA.5 subgroups compared with uninfected individuals Breakthrough infections of the variant are less likely.

Joao Marato, MA
Instituto de Medicina Molecular JoĆ£o Lobo Antunes, Lisbon, Portugal

Ruy M. Ribeiro, Doctor of Philosophy.
Los Alamos National Laboratory, Los Alamos, New Mexico

Pedro P. Leite, MD
Pedro Casaca, MD
Eugenia Fernandes, Ph.D.
DireĆ§Ć£o Geral da SaĆŗde, Lisbon, Portugal

Dr. Carlos Antunes
University of Lisbon, Lisbon, Portugal

VƔlter R. Fonseca, MD, Ph.D.
DireĆ§Ć£o Geral da SaĆŗde, Lisbon, Portugal

Dr. Manuel C. Gomes
University of Lisbon, Lisbon, Portugal

Luis Graca, MD, PhD.
Instituto de Medicina Molecular JoĆ£o Lobo Antunes, Lisbon, Portugal
[emailĀ protected]

EU support Horizon 2020 Research and Innovation Programme (ERA Project No. 952377ā€“iSTARS) and FundaĆ§Ć£o para a CiĆŖncia ea Tecnologia via 081_596653860 and PTDC/MAT-APL/31602/2017 and via National Institutes of Health Grant R01-AI116868.

The disclosure form provided by the authors and the full text of this letter are available at

This letter was published on on August 31, 2022.

PhD. Gomez and Graca contributed equally to the letter.

  1. 1. Qu Ping, Faraone, Evans JP, et al. Neutralizes SARS-CoV-2 omicron BA.4/5 and BA.2.12.1 sub-variants.New England Journal of Medicine 2022;386:25262528.

  2. 2. Yu Jie, Collier, Romi, et al. Neutralizes SARS-CoV-2 omicron BA.1 and BA.2 variants.New England Journal of Medicine 2022;386:15791580.

  3. 3. Cao Yi, Ismail A, Jian Fei, et al. BA.2.12.1, BA.4 and BA.5 evade antibodies elicited by omicron infection.nature 2022;608:593602.

  4. 4. Instituto Nacional de SaĆŗde Doutor Ricardo Jorge. Genetic diversity of the Portuguese novel coronavirus SARS-CoV-2 (COVID-19). (in Portuguese) 2022 (

  5. 5. Altalani HN, Chemetelli H, Ayub, et al. Protection of SARS-CoV-2 natural infection from reinfection with omicron BA.4 or BA.5 sub-variants. July 12, 2022 ( preprint.

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