Transmission-blocking strategies that slow the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and protect against coronavirus disease 2019 (COVID-19) are needed. We have developed an orally-delivered Adenovirus type (Ad) 5-vectored SARS-CoV-2 vaccine candidate that expresses the spike protein. Here we demonstrated that hamsters vaccinated by the oral or intranasal route had robust and cross-reactive antibody responses. We then induced a post-vaccination infection by inoculating vaccinated hamsters with SARS-CoV-2. Oral- or intranasal-vaccinated hamsters had decreased viral RNA and infectious virus in the nose and lungs and experienced less lung pathology compared to mock-vaccinated hamsters after SARS-CoV-2 challenge. Naïve hamsters exposed in a unidirectional air flow chamber to mucosally-vaccinated, SARS-CoV-2-infected hamsters also had lower nasal swab viral RNA and exhibited fewer clinical symptoms than control animals, suggesting that the mucosal-route reduced viral transmission. The same platform encoding the SARS-CoV-2 spike and nucleocapsid proteins elicited mucosal cross-reactive SARS-CoV-2-specific IgA responses in a phase 1 clinical trial (NCT04563702). Our data demonstrate that mucosal immunization is a viable strategy to decrease SARS-CoV-2 disease and airborne transmission.
Vaccines that are shelf stable and easy to administer are crucial to improve vaccine access and reduce SARS-CoV-2 transmission around the world. Here we demonstrate that an oral, adenovirus-based vaccine candidate protects against SARS-CoV-2 in a Syrian hamster challenge model. Hamsters administered two doses of VXA-CoV2-1 showed a reduction in weight loss and lung pathology and had completely eliminated infectious virus 5 days post challenge. Oral immunization induced anti-spike IgG and neutralizing antibodies were induced upon oral immunization with the sera demonstrating neutralizing activity. Overall this data demonstrates the ability of oral vaccine candidate VXA-CoV2-1 to provide protection against SARS-CoV-2 disease.
BackgroundDespite the plethora of efficacious vaccines to the initial Wuhan strain of SARS-CoV-2, these do not induce robust mucosal immunity, offering limited protection against breakthrough infection and replication in the respiratory tract. The mucosa is the first line of defense, therefore a vaccine that induces a mucosal IgA response could be an important strategy in curbing the global pandemic.MethodsWe conducted a single-site, dose-ranging, open-label clinical trial of an oral SARS-CoV-2 vaccine to determine safety and immunogenicity. This tablet vaccine is comprised of a non-replicating adenoviral vector expressing the SARS-CoV-2 Spike and Nucleocapsid genes and a double-stranded RNA adjuvant. 35 adult subjects meeting inclusion/exclusion criteria received a single low (1×1010 IU) or high (5×1010 IU) dose and 5 subjects received two low doses. Nasal, saliva and serum samples were assessed for the presence of IgA, IgG and surrogate neutralizing antibodies. Convalescent subjects between 1-8 months post infection were recruited to give nasal, saliva, and serum samples for comparison.ResultsThe vaccine was well tolerated without any dose-limiting toxicity observed. No serum neutralizing antibodies were observed, but modest IgA responses were seen in serum post immunization. The majority of vaccine recipients had an increase in mucosal secretory IgA which was highly cross-reactive against all coronaviruses tested and persisted up to 360 days. Furthermore, the nasal IgA induced by vaccination has superior neutralizing activity compared to convalescent nasal samples.ConclusionThe vaccine was safe, well tolerated and generated mucosal immune responses including cross-reactive surrogate neutralizing secretory IgA. These results demonstrate the ability of a mucosal vaccine to induce long-lasting mucosal IgA to SARS-CoV-2.Graphical Abstract
The emergence of SARS-CoV-2 variants continues to be a major obstacle for controlling the global pandemic. Despite the currently authorized SARS-CoV-2 vaccines ability to reduce severe disease and hospitalization, new immunization strategies are needed that enhance mucosal immune responses, inhibit community transmission, and provide protection against emerging variants. We have developed a mucosally delivered, non-replicating recombinant adenovirus vector (rAd5) vaccine, that has proven efficacy in the clinic against other respiratory viruses [1]. Here we evaluated the immunogenicity of three candidate SARS-CoV-2 vaccines in cynomolgus macaques that contained spike (S) and/or nucleocapsid (N) from either the Wuhan or the beta variant to select a candidate for future clinical development. Mucosal immunization with the Wuhan specific S vaccine (ED90) induced significant cross-reactive serum IgG responses against to Wuhan, beta, gamma and delta lineages, and generated substantial serum neutralizing activity. In nasal samples, ED90 immunization induced 1000-fold increases in IgA to all variants of concern tested and had neutralizing activity against Wuhan and delta. While immunization with the beta specific vaccine (ED94) enhanced IgG and IgA responses to homologous beta variant S and RBD, this approach resulted in less cross-reactive responses to other variants in the serum and nasal passages compared to ED90. As ED90 immunization induced the most robust cross-reactive systemic and mucosal antibody responses, this candidate was chosen for future clinical development.
RESUMENObjetivo.Describir las características sociodemográficas y clínico-epidemiológicas y determinar los factores asociados a la mortalidad de personas con diagnóstico de tuberculosis en Paraguay.Métodos.Investigación operativa con un diseño de cohortes retrospectivo de los casos diagnosticados con TB en Paraguay entre 2015-2016. Se utilizó la base datos del Programa Nacional de Control de Tuberculosis. Para determinar los factores asociados con mortalidad se utilizaron pruebas chi cuadrado y riesgo relativo (RR) con un intervalo de confianza de 95% (IC95%); además, se ajustó un modelo de regresión múltiple de Poisson robusto. Se utilizó un nivel de significación de 5%.Resultados.Se estudiaron 5 141 casos de TB, de los cuales 11,5% fallecieron, los factores que aumentan el riesgo de muerte fueron: sexo masculino (RR: 1,26 IC; 95%: 1,1-1,50), infección con virus de la inmunodeficiencia humana (VIH) (RR: 4,78; IC 95%: 4,04-5,65) y enfermedad pulmonar obstructiva crónica (RR: 1,70; IC 95%: 1,19-2,42). Como factor protector se identificó ser persona privada de la libertad (RR: 0,37 IC 95%: 0,24-0,61).Conclusiones.El mayor riesgo de muerte lo presentan los hombres y las personas con coinfección TB/VIH y el menor riesgo, las personas privadas de la libertad. Es necesario mejorar el diagnóstico y seguimiento a los casos de TB, con la efectiva implementación del tratamiento directamente observado (TDO) así como el manejo oportuno de enfermedades asociadas como VIH y enfermedad pulmonar obstructica crónica (EPOC).
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