José Víctor Zambrana, Ian A. Mellis, Abigail Shotwell, Hannah E. Maier, Yara Saborio, Carlos Barillas, Roger López, Gerald Vásquez, Miguel Plazaola, Nery Sánchez, Sergio Ojeda, Isabel Gilbertson, Guillermina Kuan, Qian Wang, Lihong Liu, Ángel Balmaseda, David D. Ho, Aubree Gordon
Vaccination and prior infection elicit neutralizing antibodies targeting SARS-CoV-2, yet the quantitative relationship between serum antibodies and infection risk against viral variants remains uncertain, particularly in underrepresented regions. We investigated the protective correlation of pre-exposure serum neutralizing antibody levels, employing a panel of SARS-CoV-2 pseudoviruses (Omicron BA.1, Omicron BA.2, and ancestral D614G), and Spike-binding antibody levels, with symptomatic BA.1 or BA.2 SARS-CoV-2 infections and overall infection, in 345 household contacts from a SARS-CoV-2 household cohort study in Nicaragua. A four-fold increase in homotypic-neutralizing (e.g., BA.1-neutralizing vs. BA.1 exposure) titers was correlated with protection from symptomatic infections (BA.1 protection: 28% [95%CI 12-42%]; BA.2 protection: 43% [20-62%]), and ancestral-neutralizing titers were also correlated with protection from either variant, but only at higher average levels than homotypic. Mediation analyses revealed that homotypic and D614G-neutralizing antibodies mediated protection from infection and symptomatic infection both from prior infection and vaccination. These findings underscore the importance of monitoring variant-specific antibody responses and highlight that antibodies targeting circulating strains may be more predictive of protection from infection. Nevertheless, ancestral-strain-neutralizing antibodies remain relevant as a correlate of protection. Our study emphasizes the need for continued efforts to assess antibody correlates of protection.