Omicron BA.4 and BA.5 Can’t Be Neutralized by Prior Infection

The Omicron COVID-19 variant continues to mutate, with its subvariants accounting for the majority of new infections. This week, the US Centers for Disease Control and Prevention (CDC) reported that new COVID-19 cases in the US were 87.1% BA.5, 6.6% BA.4, and 4.8% BA 4.6.

One study, published in Nature Communications, examined whether contracting a previous strain of Omicron provides sufficient protection against its new subvariants. The investigators also analyzed the efficacy of COVID-19 vaccination at neutralizing the BA.4 and BA.5 variants.

In March 2022, BA.4 and BA.5 were detected by genomic surveillance in South Africa, and subsequently led to a wave in infections. Excess all-cause mortality, previously correlated with BA.2, did not sharply increase with the emergence of BA.4 and BA.5.

The Omicron BA.4 and BA.5 sub-lineages do not differ from each other in their spike sequence, but have changes relative to the BA.1 and BA.2 strains, including L452R and F486V mutations and R493Q reversion in the spike receptor binding domain (RBD).

The investigators isolated live BA.4 and BA.5 viruses to determine whether they could be neutralized by BA.1 infection. They considered prior BA.1 infection in conjunction with COVID-19 vaccination, prior BA.1 infection alone, and COVID-19 vaccination with no infection history.

To quantify neutralization, the investigators reported 50% focus reduction neutralization test value, the inverse of the plasma dilution required for a 50% reduction in the number of infection foci relative to the no antibody control in a live virus neutralization assay.

They found that in individuals with prior BA.1 infection and no vaccination history, neutralization decreased 7.6-fold for BA.4 and 7.5-fold for BA.5. For individuals who were fully vaccinated and had contracted BA.1, neutralization capabilities dropped 3.2-fold for BA.4, and 2.6-fold for BA.5. Their fold-drop versus ancestral virus neutralization was 4.0-fold for BA.1, 12.9-fold for BA.4, and 10.3-fold for BA.5.

Finally, vaccinated individuals with no prior infection saw BA.4 and BA.5 escape neutralization at rates similar to BA.1. Fold-drop relative to the ancestral COVID-19 virus was 19.8-fold for BA.1, 19.6-fold for BA.4, and 20.9-fold for BA.5.

From these results, the investigators determined BA.4 and BA.5 significantly evaded the immunity generated by a prior BA.1 infection, even in conjunction with COVID-19 vaccination. BA.4 and BA.5 were especially adept at avoiding neutralization in BA.1-infected, unvaccinated individuals.

The study highlights the necessity of addition booster vaccination, potentially with the impending variant-specific booster shots expected this fall.