Just 10 months after the initial genome sequencing of the SARS-CoV-2 virus, two mRNA vaccines were demonstrated to provide 95% efficacy against symptomatic infections via randomized, placebo-controlled trials of more than 74,000 participants (1). That unprecedented success was, in part, fueled by the $10 billion governmental investment in Operation Warp Speed (OWS) in March 2020 to accelerate the development, manufacturing, and distribution of COVID-19-19 vaccines. We urgently need such an accelerated initiative now for nasal vaccines.
During the first year of the pandemic, meaningful evolution of the virus was slow-paced, without any functional consequences, but since that time we have seen a succession of important variants of concern, with increasing transmissibility and immune evasion, culminating in the Omicron lineages. With that, there has been a dramatic falloff in the capacity for vaccinations and booster shots to block infections and transmission (2). A major unmet clinical need has arisen to block the transmission chain, prevent the frequent breakthrough infections, and achieve high levels of durable protection against severe disease, no less prevent post-acute sequelae of SARS-CoV-2 infection (PASC, Long COVID-19).
That has spotlighted the possibility of nasal vaccines, with their allure for achieving mucosal immunity, complementing, and likely bolstering the circulating immunity achieved via intramuscular shots. A new report by Tang and colleagues (3) sheds considerable light on the shortcomings of mRNA vaccines for not achieving respiratory mucosal immunity against Omicron in people, while also showing how well this can be accomplished with a nasal vaccine in mice.
Beyond the conventional parameters of circulating antibodies, B and T cell immunity in the blood, this elegant study assessed bronchoalveolar lavage (BAL) fluid immunity to specifically characterize the lower respiratory mucosa, tissue-resident memory B and T cells that are part and parcel of protection. In the human part of the study, 19 vaccinated participants were compared with 10 who had convalesced from COVID-19 and 5 who were unvaccinated. Notably, the mean age of the participants was 70 years and similar for the three groups. The vaccinated group, despite having comparable circulating neutralizing antibodies against D614G, delta, and omicron variants, had significantly lower neutralizing titers against all variants in the BAL compared to the convalescent group. Moreover, the vaccinated group had substantially fewer BAL tissue-resident spike-specific memory CD4 T, CD8 T, and RBD-specific memory B cells than the group with prior COVID-19. These observations are an important addition to other studies that have reported superior mucosal (saliva) antibodies in those with prior COVID-19 than vaccinated individuals (4) and the establishment of tissue-resident T cells for up to 6 months after infection (5).

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