Coordinated early immune response in the lungs is required for effective control of SARS-CoV-2 replication

Introduction

Immunity conferred by infection or widespread vaccination jointly reduced the impact of the SARS-CoV-2 pandemic. The extent of infections with the Delta and Omicron variants led to most individuals today having a combination of infection- and vaccine-derived immunity, described as hybrid immunity^1,2. Prior infection enhances the vaccine response by increasing the potency and breadth of systemic antibodies and augmenting mucosal immunity, particularly virus-specific IgA responses^{3, 4, 5, 6–7}. In epidemiological studies, hybrid immunity also provided increased protection against infection with Omicron variants compared to vaccination or prior infection alone^{8, 9, 10, 11, 12–13}.

However, observational studies of SARS-CoV-2 hybrid immunity in humans are increasingly difficult due to the high diversity of past exposures through vaccination and infection with different variants. Abortive and asymptomatic infections, when the individuals are unaware of their complete infection history, add another layer of complexity¹⁴. On the other hand, controlled SARS-CoV-2 exposures in non-human primate (NHP) studies provide an opportunity to dissect the responses at mucosal sites in addition to the periphery for a comprehensive view of the elicited immunity.

Emergence of SARS-CoV-2 Omicron in November 2021 raised concerns about viral escape with >30 mutations in the Spike (S) protein¹⁵ and considerable loss of neutralizing activity in vaccinated individuals¹⁶. This prompted an update of existing vaccines to better match circulating variants, leading to the licensing of WA-1/BA.5 bivalent booster mRNA vaccines in the fall of 2022. Meanwhile, an XBB Omicron lineage started to prevail in Europe and North America. This lineage arose through recombination of BA.2.10.1 and BA.2.75 and has shown one of the highest immune evasion rates to date^{17, 18–19}. Nevertheless, the risk of severe outcomes was reduced during the post-Omicron era compared to the earlier variants, owing to an intrinsic reduction in disease severity as well as substantial pre-existing immunity in the population^20,21.

In uninfected vaccinated individuals, neutralizing antibodies in the serum are highly associated with protection from infection^{22, 23–24}. However, the rapid viral evolution led to a significant reduction in neutralization potency^{17, 18–19}, and broadly neutralizing antibodies are rarely elicited in protective quantities^25,26. The specificity of B cell responses has been suggested to be imprinted by...