The gradient of the high efficacy of nirmatrelvir/ritonavir (Paxlovid) for SARS-CoV-2 to the relatively low efficacy of oseltamivir (Tamiflu) for influenza is noteworthy. Recall that COVID-19 vaccines had an initial efficacy of 95% against symptomatic infections and severe disease, a level that was never approximated by flu shots. However, in many ways, influenza represents a different and more formidable challenge than SARS-CoV-2, with the hypermutating feature of its hemagglutinin head and immune evasion propensity of its stem. Although it is now quadrivalent and has efficacy comparable with flu shots (which is moderate at best), the approval population is limited (for example, not for age 50 years and older, and excludes immunocompromised and pregnant people). FluMist, reformulated in 2018, is the only intranasal vaccine approved by the Food and Drug Administration.
Similar findings of elevated mucosal IgA and tissue-resident memory cells were reported after an unadjuvanted recombinant spike protein nasal booster strategy after mRNA prime ( 6).ĭespite these encouraging data, we fully recognize the challenges of validating a clinically effective and safe nasal vaccine for which there has been limited success in the past. Supporting the mucosal immunity achieved via intranasal delivery, there were marked increases in the BAL of S-1 and RBD-specific IgA levels and tissue-resident T cell immunity after nasal booster with recombinant spike or AD5-S. This was true against both the ancestral strain and the Omicron BA.1.1 lineage. Only weak neutralizing antibodies were induced in the BAL by intramuscular shots and nasal spike trimer + cGAMP, in contrast to very high levels when AD5-S was administered nasally.
VACCINE COVID PLUS
In the mouse model experiments, a booster dose consisting of intramuscular mRNA, intranasal recombinant spike trimer protein plus cGAMP adjuvant (a STING agonist), or intranasal adenovirus-vector encoding the ancestral spike (AD5-S) was administered to mice previously vaccinated with two doses of intramuscular mRNA vaccine shots. These observations are an important addition to other studies that have reported superior mucosal (saliva) antibodies in those with prior COVID-19 compared with vaccinated individuals ( 4) and the establishment of tissue-resident T cells for up to 6 months after infection ( 5). 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.
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 with the convalescent group. Notably, the mean age of the participants was 70 years and similar for the three groups. 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. Beyond the conventional parameters of circulating antibodies, and 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.
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