Hybrid immunity and strategies for COVID-19 vaccination

Since April, 2022, BA.2.12.1, BA.4, and BA.5 subvariants of the omicron (B.1.1.529) SARS-CoV-2 variant of concern have been spreading globally with increased viral fitness and transmissibility. Omicron BA.5 subvariant is currently the predominant COVID-19 threat worldwide.¹ With the emergence of the antigenically distinct variants of concern, either natural immunity or first-generation vaccine-induced immunity has failed to prevent transmission effectively. Booster (third or fourth) doses of vaccine play an important role in preventing symptomatic infection, although the boosting effect only lasts for several months.² Hybrid immunity refers to the immune protection in individuals who have had one or more doses of a COVID-19 vaccine and at least one SARS-CoV-2 infection before or after the first vaccination.³

In The Lancet Infectious Diseases, Sara Carazo and colleagues⁴ report the findings of a novel study based on a dataset derived from health-care workers during the omicron BA.1 surge among the highly vaccinated Quebec population. The study used a test-negative case-control design and compared health-care workers who had a positive SARS-CoV-2 nucleic acid amplification test (cases) during the period of omicron BA.2 dominance from March 27 to June 4, 2022, versus health-care workers who had a negative test during the same period (controls). The data consisted of a large pool with potential hybrid immunity resulting from combined vaccination and natural infection. The authors found that previous BA.1 infection was the most protective factor against BA.2 infection (associated with a risk reduction of 72%), and gave greater protection than primary infection with pre-omicron SARS-CoV-2 (38%) or three doses of mRNA vaccine in individuals with no previous primary infection (46%). Hybrid immunity from BA.1 infection plus two to three vaccine doses similarly increased the estimated effectiveness to 96% for longer than 5 months.⁴

In a national, matched, test-negative, case-control study in Qatar from Dec 23, 2021, to Feb 21, 2022, no differences in protection against symptomatic BA.1 and BA.2 infection were noted between people with previous infection, people who had been vaccinated with two doses of BNT162b2, and people with hybrid immunity.² Vaccination with a BNT162b2 booster enhanced protection among people who had previous infection. Hybrid immunity resulting from previous infection and a booster vaccination within 8 months after the second dose conferred the strongest protection against symptomatic BA.1 or BA.2 infection. Additionally, previous infection and two to three vaccine doses with or without previous infection conferred strong protection (risk reduction of >96%) against severe, critical, or fatal BA.1 infection. By contrast, previous infection (73·4%) or two doses of vaccine (76·8%) gave weaker protection, while two to three vaccine doses with or without previous infection conferred stronger protection (>97%), against severe, critical, or fatal BA.2 infection.²

More specific data on BA.4 and BA.5 subvariants are now available. In an in-vitro study evaluating pseudovirus neutralising antibody titres against the original wild-type isolate of SARS-CoV-2 along with omicron subvariants BA.1, BA.2, BA.2.12.1, and BA.4 or BA.5 in 27 participants who had been vaccinated with three doses of mRNA vaccine BNT162b2, and in 27 participants who had previous infection with the BA.1 or BA.2 subvariant a median of 29 days earlier, the investigators found that the BA.2.12.1, BA.4, and BA.5 subvariants substantially escaped neutralising antibodies induced by both vaccination and infection. Moreover, neutralising antibody titres against the BA.4 or BA.5 subvariant and against the BA.2.12.1 subvariant were lower than titres against the BA.1 and BA.2 subvariants, which suggests that the SARS-CoV-2 omicron variant has continued to evolve with increasing neutralisation escape.⁵ A study in Portugal using the national COVID-19 registry to estimate the risk of BA.5 infection among people with documented infection with past SARS-CoV-2 variants, including BA.1 and BA.2, has shown that BA.1 or BA.2 infection in vaccinated people provided higher protection (risk reduction of 75·3%) against BA.5 infection than did infection with pre-omicron variants (wild type 51·6%, alpha [B.1.1.7] 54·8%, and delta [B.1.617.2] 61·3%), in line with the two studies with a test-negative design.2, 4 Overall, the data suggested that breakthrough infections with the BA.5 subvariant were less likely to occur among people with a previous SARS-CoV-2 infection history in a highly vaccinated population, especially for previous BA.1 or BA.2 infection, than among people with no previous primary infection.⁶

These data provide immunological context for the importance of hybrid immunity in managing the current surges caused by the BA.2.12.1, BA.4, and BA.5 subvariants in populations with high frequencies of vaccination and BA.1 or BA.2 infection.2, 3, 4, 5, 6 Another important factor in reducing infection risk is heterologous booster vaccination with different platforms to maximise the breadth of vaccine-induced immunity, especially in countries primarily using inactivated vaccine; T-cell immunity is not affected by changes in spike protein and remains effective in preventing severe disease, hospitalisation, and death.7, 8, 9 Finally, second-generation BA.4 or BA.5-based vaccines should be considered in managing the current threat due to the widely circulating BA.5 variant.¹⁰

© 2023 Flickr - Jernej Furman

I declare no competing interests.