We evaluated the immunogenicity and protective ability of a chimpanzee replication-deficient adenovirus vectored COVID-19 vaccine (BV-AdCoV-1) expressing a stabilized pre-fusion SARS-CoV-2 spike glycoprotein in golden Syrian hamsters. Intranasal administration of BV-AdCoV-1 elicited strong humoral and cellular immunity in the animals. Furthermore, vaccination prevented weight loss, reduced SARS-CoV-2 infectious virus titers in the lungs as well as lung pathology and provided protection against SARS-CoV-2 live challenge. In addition, there was no vaccine-induced enhanced disease nor immunopathological exacerbation in BV-AdCoV-1-vaccinated animals. Furthermore, the vaccine induced cross-neutralizing antibody responses against the ancestral strain and the B.1.617.2, Omicron(BA.1), Omicron(BA.2.75) and Omicron(BA.4/5) variants of concern. These results demonstrate that BV-AdCoV-1 is potentially a promising candidate vaccine to prevent SARS-CoV-2 infection, and to curtail pandemic spread in humans.

Current COVID-19 vaccines are effective countermeasures to control the SARS-CoV-2 virus pandemic by inducing systemic immune responses through intramuscular injection. However, respiratory mucosal immunization will be needed to elicit local sterilizing immunity to prevent virus replication in the nasopharynx, shedding, and transmission. In this study, we first compared the immunoprotective ability of a chimpanzee replication–deficient adenovirus–vectored COVID-19 vaccine expressing a stabilized pre–fusion spike glycoprotein from the ancestral SARS-CoV-2 strain Wuhan–Hu–1 (BV-AdCoV-1) administered through either aerosol inhalation, intranasal spray, or intramuscular injection in cynomolgus monkeys and rhesus macaques. Compared with intranasal administration, aerosol inhalation of BV-AdCoV-1 elicited stronger humoral and mucosal immunity that conferred excellent protection against SARS-CoV-2 infection in rhesus macaques. Importantly, aerosol inhalation induced immunity comparable to that obtained by intramuscular injection, although at a significantly lower dose. Furthermore, to address the problem of immune escape variants, we evaluated the merits of heterologous boosting with an adenovirus–based Omicron BA.1 vaccine (C68–COA04). Boosting rhesus macaques vaccinated with two doses of BV-AdCoV-1 with either the homologous or the heterologous C68–COA04 vector resulted in cross–neutralizing immunity against WT, Delta, and Omicron subvariants, including BA.4/5 stronger than that obtained by administering a bivalent BV-AdCoV-1/C68–COA04 vaccine. These results demonstrate that the administration of BV-AdCoV-1 or C68–COA04 via aerosol inhalation is a promising approach to prevent SARS-CoV-2 infection and transmission and curtail the pandemic spread.

Human papillomavirus (HPV) is a prevalent cause of mucosal and cutaneous infections and underlying conditions ranging from benign warts to anogenital and oropharyngeal cancers affecting both males and females, notably cervical cancer. Cervical cancer is the fourth leading cause of cancer deaths among women globally and is the most impactful in low- and middle-income countries (LMICs), where the costs of screening and licensed L1-based HPV vaccines pose significant barriers to comprehensive administration. Additionally, the licensed L1-based HPV vaccines fail to protect against all oncogenic HPV types. This study generated three independent lots of an L2-based target antigen (LBTA), which was engineered from conserved linear L2-protective epitopes (aa11–88) from five human alphapapillomavirus genotypes in E. coli under cGMP conditions and adjuvanted with aluminum phosphate. Vaccination of rabbits with LBTA generated high neutralizing antibody titers against all 17 HPV types tested, surpassing the nine types covered by Gardasil^®9. Passive transfer of naïve mice with LBTA antiserum revealed its capacity to confer protection against vaginal challenge with all 17 αHPV types tested. LBTA shows stability at room temperature over >1 month. Standard in vitro and in vivo toxicology studies suggest a promising safety profile. These findings suggest LBTA’s promise as a next-generation vaccine with comprehensive coverage aimed at reducing the economic and healthcare burden of cervical and other HPV+ cancers in LMICs, and it has received regulatory approval for a first-in-human clinical study (NCT05672966).

Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants, young children, and the elderly. Current licensed prefusogenic F-based RSV vaccines induce systemic immune responses through intramuscular injection. However, mucosal immunization will be required to elicit local sterilizing immunity to prevent virus replication in the nasopharynx and the lungs as well as virus shedding and transmission. Adenovirus vectors are a promising platform to develop RSV vaccines, but further evaluation of mucosal adenovirus-based prefusion F (preF) vaccines is still needed. In this study, we constructed a recombinant chimpanzee adenovirus serotype 68 vector expressing a second-generation disulfide-stabilized (DS2)trimeric preF protein (ChAd68-PreF). In mice, intranasal immunization with ChAd68-PreF induced dose-dependent increase in RSV-specific secretory IgA (sIgA) in the lower respiratory tract, demonstrating its capacity to elict mucosal immunity. Subsequently, in cotton rats, intratracheal instillation of ChAd68-PreF induced high cross-neutralizing antibody titers against RSV A and RSV B. After RSV A2 challenge, ChAd68-PreF vaccinated animals showed no detectable viral replication in the nose nor in the lungs. Moreover, ChAd68-PreF vaccination did not lead to enhanced respiratory disease (ERD) in cotton rats. These results demonstrate that mucosal delivery of ChAd68-PreF confers potent protective immunity against RSV with good safety profile, warranting further clinical development as a mucosa-targeting RSV vaccine for vulnerable populations.