Humoral Immunity and Variant Cross-Reactivity Following Asymptomatic and Symptomatic SARS-CoV-2 Infection and Vaccination in Young Adults (The ACE Cohort)

Abstract Purpose Asymptomatic SARS-CoV-2 infection was a driving force of the COVID-19 pandemic, acting as a silent transmitter of the virus. The question of whether asymptomatic immunity differs from symptomatic immunity remains, as existing studies fail to recruit ‘well-defined’ asymptomatic individuals. Here, we conducted a longitudinal cohort study to evaluate humoral responses to infection and vaccination in asymptomatic predominantly young adults identified as part of the Asymptomatic COVID-19 in Education [ACE] cohort. Methods Asymptomatic testing services, located at three UK universities, identified asymptomatic adults who were subsequently recruited with age- and sex-matched symptomatic and uninfected controls. Blood and saliva samples were collected after SARS-CoV-2 Wuhan infection, and again after vaccination. Over 500 participants were recruited, and their IgG and IgA titres were measured in response to 5 Variants of Concern. Results Pre-vaccination, asymptomatic individuals exhibit significantly lower IgG responses to four of the tested variants; Wuhan, Alpha, Beta, and Delta, compared to symptomatic individuals; these differences diminished post-vaccination. In addition, there were key differences in terms of IgG cross-reactivity, where symptomatic individuals displayed stronger IgG cross-reactivity than asymptomatic and uninfected individuals, alluding to better protection from emerging variants. Individuals without prior natural infection displayed reduced IgG responses compared to symptomatic individuals, to all variants, post-vaccination. Despite their low IgG, salivary IgA levels in uninfected individuals were high, pre-vaccination. Conclusion This work demonstrates the requirement of vaccinations to enhance weaker IgG responses but also highlights that vaccines need to be constantly adapted to overcome viral evolution, particularly with more done to improve mucosal delivery options for respiratory viruses to enhance IgA responses.