Immunological drivers of the transition from epidemicity to endemicity of SARS-CoV-2 in a high transmission LMIC setting

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Principal Investigator: Federico  Costa
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $741,011
Funding agency: National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY
Although new variants may contribute to surges, we expect SARS-CoV-2 to transition to a new phase where
the virus continues to circulate but at lower levels. Sequential immunizing exposures, whether due to infection
or vaccination, have transformed the immune status of populations by cumulatively increasing antibody levels
and increasing the breadth of antigenic targeting of SARS-CoV-2 by antibodies. The relative role of increased
magnitude of antibody responses or broadening of antigenic recognition of SARS-CoV-2 in protecting
populations from infection is not known. Strikingly, though mucosal responses have been found to play key
roles in protecting individuals from infection, SARS-CoV-2 literature has focused almost exclusively on
serological responses. Effective policy and investment in public health measures as the pandemic continues
will require information on the relative importance of specific immune responses. Gathering evidence in diverse
settings including low and middle income countries (LMIC) is particularly important as the immunizing exposure
history in these settings has been different (in terms of infections and vaccine use) and a smaller evidence
base is available from these settings. Our proposed work seeks to continue to interrogate SARS-CoV-2
immunity in a cohort residing in an urban slum community in Brazil which we have followed since 2003. We
identified an extraordinarily high SARS-CoV-2 attack rate (75%) during two epidemic waves with D614G and
Gamma variants. Subsequent vaccination has generated hybrid immunity in a large proportion of our cohort.
Our proposed study would investigate the relative role of antibody magnitude and breadth within systemic and
mucosal compartments in protecting this population from infection. To accomplish this, we propose to conduct
serologic and virologic surveillance in this community and develop tools to interpret serological measures of
infection that address a key epidemiological challenge for the world in continued characterization of infection
during the next phase of the pandemic. Our proposal leverages a 27-year scientific collaboration with the
Brazilian Ministry of Health, an extensive track record of interrogating SARS-CoV-2 immunity, novel assays
and analytical methods to infer infection histories and characterize multi-antigen immune responses. Our study
will generate key evidence to inform the development of novel vaccines (intranasal, multi-antigen) and a new
approach to tracking SARS-CoV-2 infections in populations with pre-existing immunity where symptom-based
virologic surveillance may give an insufficient view of viral transmission.

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