Cardoso Kimberly Freitas, de Souza Lara Regina Alves, da Silva Santos Beatriz Senra Álvares, de Carvalho Ketyllen Reis Andrade, da Silva Messias Sarah Giarola, de Faria Gonçalves Ana Paula, Kano Flora Satiko, Alves Pedro Augusto, da Silva Campos Marco Antônio, Xavier Marcelo Pascoal, Garcia Cristiana Couto, Russo Remo Castro, Gazzinelli Ricardo Tostes, Costa Érica Azevedo, da Silva Martins Nelson Rodrigo, Miyaji Eliane Namie, de Magalhães Vieira Machado Alexandre, Silva Araújo Márcio Sobreira
Laboratório de Imunologia de Doenças Virais, Instituto René Rachou-Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brasil.
Grupo Integrado de Pesquisa em Biomarcadores, Instituto René Rachou-Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brasil.
NPJ Vaccines. 2024 Dec 19;9(1):246. doi: 10.1038/s41541-024-01033-5.
Streptococcus pneumoniae and influenza A virus (IAV) are significant agents of pneumonia cases and severe respiratory infections globally. Secondary bacterial infections, particularly by Streptococcus pneumoniae, are common in IAV-infected individuals, leading to critical outcomes. Despite reducing mortality, pneumococcal vaccines have high production costs and are serotype specific. The emergence of new circulating serotypes has led to the search for new prevention strategies that provide a broad spectrum of protection. In this context, vaccination using antigens present in all serotypes, such as Pneumococcal Surface Protein A (PspA), can offer broad coverage regardless of serotype. Employing the reverse genetics technique, our research group developed a recombinant influenza A H1N1 virus that expresses PspA (Flu-PspA), through the replacement of neuraminidase by PspA. This virus was evaluated as a bivalent vaccine against infections caused by influenza A and S. pneumoniae in mice. Initially, we evaluated the Flu-PspA virus's ability to infect cells and express PspA in vitro, its capacity to multiply in embryonated chicken eggs, and its safety when inoculated in mice. Subsequently, the protective effect against influenza A and Streptococcus pneumoniae lethal challenge infections in mice was assessed using different immunization protocols. Analysis of the production of antibodies against PspA4 protein and influenza, and the binding capacity of anti-PspA4 antibodies/complement deposition to different strains of S. pneumoniae were also evaluated. Our results demonstrate that the Flu-PspA virus vaccine efficiently induces PspA protein expression in vitro, and that it was able to multiply in embryonated chicken eggs even without exogenous neuraminidase. The Flu-PspA-based bivalent vaccine was demonstrated to be safe, stimulated high titers of anti-PspA and anti-influenza antibodies, and protected mice against homosubtypic and heterosubtypic influenza A and S. pneumoniae challenge. Moreover, an efficient binding of antibodies and complement deposition on the surface of pneumococcal strains ascribes the broad-spectrum vaccine response in vivo. In summary, this innovative approach holds promise for developing a dual-protective vaccine against two major respiratory pathogens.
肺炎链球菌和甲型流感病毒（IAV）是全球肺炎病例和严重呼吸道感染的重要病原体。继发性细菌感染，尤其是肺炎链球菌引起的感染，在IAV感染个体中很常见，会导致严重后果。尽管肺炎球菌疫苗降低了死亡率，但生产成本高昂且具有血清型特异性。新的流行血清型的出现促使人们寻找能提供广泛保护的新预防策略。在这种背景下，使用所有血清型中都存在的抗原（如肺炎球菌表面蛋白A，PspA）进行疫苗接种，无论血清型如何，都能提供广泛的覆盖范围。利用反向遗传学技术，我们的研究小组通过用PspA替代神经氨酸酶，开发出了一种表达PspA的重组甲型H1N1流感病毒（Flu-PspA）。该病毒作为一种二价疫苗，在小鼠中针对甲型流感和肺炎链球菌感染进行了评估。首先，我们评估了Flu-PspA病毒在体外感染细胞和表达PspA的能力、在鸡胚中繁殖的能力以及接种到小鼠体内时的安全性。随后，使用不同的免疫方案评估了其对小鼠甲型流感和肺炎链球菌致死性攻击感染的保护作用。还评估了针对PspA4蛋白和流感的抗体产生情况，以及抗PspA4抗体/补体沉积对不同肺炎链球菌菌株的结合能力。我们的结果表明，Flu-PspA病毒疫苗在体外能有效诱导PspA蛋白表达，并且即使没有外源性神经氨酸酶也能在鸡胚中繁殖。基于Flu-PspA的二价疫苗被证明是安全的，能刺激产生高滴度的抗PspA和抗流感抗体，并保护小鼠免受同亚型和异亚型甲型流感以及肺炎链球菌的攻击。此外，抗体在肺炎球菌菌株表面的有效结合和补体沉积归因于体内的广谱疫苗反应。总之，这种创新方法有望开发出针对两种主要呼吸道病原体的双重保护疫苗。
