Mucosal vaccination for SARS-CoV-2 elicits superior systemic T central memory function and cross-neutralizing antibodies against variants of concern

COVID-19 vaccines used in humans are highly effective in limiting disease and death caused by the SARS-CoV-2 virus, yet improved vaccines that provide greater protection at mucosal surfaces, which could reduce break-through infections and subsequent transmission, are still needed. Here we show that intranasal (I.N.) vaccination with the receptor binding domain of Spike antigen of SARS-CoV-2 (S-RBD) in combination with the mucosal adjuvant mastoparan-7 improved systemic T cell responses compared to an equivalent dose of antigen delivered by the sub-cutaneous (S.C.) route, adjuvanted by either M7 or the gold-standard adjuvant, alum. T cell phenotypes induced by I.N. vaccine administration included enhanced polyfunctionality (combined IFN-{gamma} and TNF expression) and greater numbers of T central memory (TCM) cells. These phenotypes were T cell-intrinsic and could be recalled in the lungs and/or brachial LNs upon antigen challenge after adoptive T cell transfer to naive recipients. Furthermore, mucosal vaccination induced antibody responses that were similarly effective in neutralizing the binding of the parental strain of S-RBD to its ACE2 receptor, but showed greater cross-neutralizing capacity against multiple variants of concern (VOC), compared to S.C. vaccination. These results highlight the role of nasal vaccine administration in imprinting an immune profile associated with long-term T cell retention and diversified neutralizing antibody responses, which could be applied to improve vaccines for COVID-19 and other infectious diseases.

Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine

The SARS-CoV-2 global pandemic has fuelled the generation of vaccines at an unprecedented pace and scale. However, many challenges remain, including: the emergence of vaccine-resistant mutant viruses, vaccine stability during storage and transport, waning vaccine-induced immunity, and concerns about infrequent adverse events associated with existing vaccines. Here, we report on a protein subunit vaccine comprising the receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein, dimerised with an immunoglobulin IgG1 Fc domain. These were tested in conjunction with three different adjuvants: a TLR2 agonist R4-Pam2Cys, an NKT cell agonist glycolipid -Galactosylceramide, or MF59(R) squalene oil-in-water adjuvant. Each formulation drove strong neutralising antibody (nAb) responses and provided durable and highly protective immunity against lower and upper airway infection in mouse models of COVID-19. We have also developed an RBD-human IgG1 Fc vaccine with an RBD sequence of the highly immuno-evasive beta variant (N501Y, E484K, K417N). This beta variant RBD vaccine, combined with MF59(R) adjuvant, induced strong protection in mice against the beta strain as well as the ancestral strain. Furthermore, when used as a third dose booster vaccine following priming with whole spike vaccine, anti-sera from beta-RBD-Fc immunised mice increased titres of nAb against other variants including alpha, delta, delta+, gamma, lambda, mu, and omicron BA.1 and BA.2. These results demonstrated that an RBD-Fc protein subunit/MF59(R) adjuvanted vaccine can induce high levels of broad nAbs, including when used as a booster following prior immunisation of mice with whole ancestral-strain Spike vaccines. This vaccine platform offers a potential approach to augment some of the currently approved vaccines in the face of emerging variants of concern, and it has now entered a phase I clinical trial.

Virological and serological kinetics of SARS-CoV-2 Delta variant vaccine-breakthrough infections: a multi-center cohort study

ObjectivesHighly effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed but variants of concerns (VOCs) with mutations in the spike protein are worrisome, especially B.1.617.2 (Delta) which has rapidly spread across the world. We aim to study if vaccination alters virological and serological kinetics in breakthrough infections. MethodsWe conducted a multi-centre retrospective cohort study of patients in Singapore who had received a licensed mRNA vaccine and been admitted to hospital with B.1.617.2 SARS-CoV-2 infection. We compared the clinical features, virological and serological kinetics (anti-nucleocapsid, anti-spike and surrogate virus neutralization titres) between fully vaccinated and unvaccinated individuals. ResultsOf 218 individuals with B.1.617.2 infection, 84 had received a mRNA vaccine of which 71 were fully vaccinated, 130 were unvaccinated and 4 received a non-mRNA. Despite significantly older age in the vaccine breakthrough group, the odds of severe COVID-19 requiring oxygen supplementation was significantly lower following vaccination (adjusted odds ratio 0.07 95%CI: 0.015-0.335, p=0.001). PCR cycle threshold (Ct) values were similar between both vaccinated and unvaccinated groups at diagnosis, but viral loads decreased faster in vaccinated individuals. Early, robust boosting of anti-spike protein antibodies was observed in vaccinated patients, however, these titers were significantly lower against B.1.617.2 as compared with the wildtype vaccine strain. ConclusionThe mRNA vaccines are highly effective at preventing symptomatic and severe COVID-19 associated with B.1.617.2 infection. Vaccination is associated with faster decline in viral RNA load and a robust serological response. Vaccination remains a key strategy for control of COVID-19 pandemic.