Mucosal Vaccines, Sterilizing Immunity, and the Future of SARS-CoV-2 Virulence

Abstract

Sterilizing immunity after vaccination is desirable to prevent the spread of infection from vaccinees, which can be especially dangerous in hospital settings while managing frail patients. Sterilizing immunity requires neutralizing antibodies at the site of infection, which for respiratory viruses such as SARS-CoV-2 implies the occurrence of neutralizing IgA in mucosal secretions. Systemic vaccination by intramuscular delivery induces no or low-titer neutralizing IgA against vaccine antigens. Mucosal priming or boosting, is needed to provide sterilizing immunity. On the other side of the coin, sterilizing immunity, by zeroing interhuman transmission, could confine SARS-CoV-2 in animal reservoirs, preventing spontaneous attenuation of virulence in humans as presumably happened with the endemic coronaviruses. We review here the pros and cons of each vaccination strategy, the current mucosal SARS-CoV-2 vaccines under development, and their implications for public health.

A live attenuated vaccine confers superior mucosal and systemic immunity to SARS-CoV-2 variants

“…Accordingly, tissue-resident memory cells undergo faster recall responses, as their local positioning allows for earlier cognate antigen recognition ( 25 ). Hence, vaccines effectively administered via the respiratory entry route, are expected to induce robust local mucosal immunity against the targeted pathogen ( 26 , 27 ).…”

Risk Stratification of SARS-CoV-2 Breakthrough Infections Based on an Outbreak at a Student Festive Event

“…One example of this “sterilizing immunity” is the vaccine against measles, mumps, and rubella. Currently approved SARS-CoV-2 vaccines do not provide sterilizing immunity against COVID-19 [ 34 ]. This is consistent with reports on waned efficiencies of the approved vaccines in the delta surge [ 35 , 36 , 37 ].…”

A bacteriophage-based, highly efficacious, needle and adjuvant-free, mucosal COVID-19 vaccine

“…The sticky mucous layers in the nasal epithelia present barriers to pathogens and possibly interfere with the ability of vaccines to access and activate the mucosal immune system. This may account for poor immunogenicity of most injectable vaccines when administered intranasally (Focosi et al, 2022; Tiboni et al, 2021). At present, of 195 COVID-19 vaccine candidates in clinical trials, only fourteen are intranasal vaccines.…”

“…Considering the evolutionary path of the virus, the most desired next-generation vaccine(s) would be one that can induce strong mucosal immunity, in addition to broader systemic immunity (Alu et al, 2022; Chavda et al, 2021; Focosi et al, 2022; Lavelle and Ward, 2021). Elicitation of target-specific mucosal antibodies at the portal of virus entry would block virus acquisition as well as shedding of infectious virus particles and their potential transmission (Afkhami et al, 2022; Bricker et al, 2021; Hassan et al, 2020; Hassan et al, 2021; Ku et al, 2021; Sterlin et al, 2021b; van Doremalen et al, 2021b).…”