Parainfluenza Virus 5 Priming Followed by SIV/HIV Virus-Like-Particle Boosting Induces Potent and Durable Immune Responses in Nonhuman Primates

Abstract

The search for a preventive vaccine against HIV infection remains an ongoing challenge, indicating the need for novel approaches. Parainfluenza virus 5 (PIV5) is a paramyxovirus replicating in the upper airways that is not associated with any animal or human pathology. In animal models, PIV5-vectored vaccines have shown protection against influenza, RSV, and other human pathogens. Here, we generated PIV5 vaccines expressing HIV envelope (Env) and SIV Gag and administered them intranasally to macaques, followed by boosting with virus-like particles (VLPs) containing trimeric HIV Env. Moreover, we compared the immune responses generated by PIV5-SHIV prime/VLPs boost regimen in naïve vs a control group in which pre-existing immunity to the PIV5 vector was established. We demonstrate for the first time that intranasal administration of PIV5-based HIV vaccines is safe, well-tolerated and immunogenic, and that boosting with adjuvanted trimeric Env VLPs enhances humoral and cellular immune responses. The PIV5 prime/VLPs boost regimen induced robust and durable systemic and mucosal Env-specific antibody titers with functional activities including ADCC and neutralization. This regimen also induced highly polyfunctional antigen-specific T cell responses. Importantly, we show that diminished responses due to PIV5 pre-existing immunity can be overcome in part with VLP protein boosts. Overall, these results establish that PIV5-based HIV vaccine candidates are promising and warrant further investigation including moving on to primate challenge studies.

Parainfluenza virus 5 is a next‐generation vaccine vector for human infectious pathogens

“…The ability of PIV5 to induce a cellular immune response was evaluated in a variety of PIV5‐based vaccine candidates. Notably, a PIV5‐vectored HIV vaccine induced highly polyfunctional antigen‐specific CD4 + and CD8 + T‐cell responses in monkeys 92 . Similarly, for a PIV5 vector influenza vaccine, the vaccine was immunogenic, prompting high levels of T‐cell responses in mice 82 .…”

“…Notably, a PIV5-vectored HIV vaccine induced highly polyfunctional antigen-specific CD4 + and CD8 + T-cell responses in monkeys. 92 Similarly, for a PIV5 vector influenza vaccine, the vaccine was immunogenic, prompting high levels of T-cell responses in mice. 82 In general, T-cell responses peaked at around 14 days following immunization, indicating a quick initiation of measurable immunological responses.…”

COVID-19 vaccine development based on recombinant viral and bacterial vector systems: combinatorial effect of adaptive and trained immunity

“…It has been reported as the second most common pathogen that causes respiratory diseases in children under 5 years of age (Álvarez-Argüelles et al, 2018). Parainfluenza virus type 5 (PIV5) has been effectively used as an efficient viral vector for protection against respiratory infections, including influenza virus, influenza A H5N1 virus, rabies virus, respiratory syncytial virus and Mycobacterium tuberculosis (Chen et al, 2015;Xiao et al, 2021). Unlike positive single-stranded RNA viruses, the PIV5 vector is stable and has a low frequency of mutation in host cells.…”

“…Newcastle disease virus (NDV) vector: Newcastle disease virus (NDV) belongs to the Paramyxoviridae family and was first identified in Indonesia in 1926. Although its zoonoses are associated with birds, this virus rarely causes influenza-like symptoms in humans (Xiao et al, 2021). Since there is no preexisting immunity against NDV in humans, the NDV vector has been considered a safe gene delivery platform due to host range restriction.…”

Efficacy of Parainfluenza Virus 5 (PIV5)-vectored Intranasal COVID-19 Vaccine as a Single Dose Vaccine and as a Booster against SARS-CoV-2 Variants

“…Previously, recombinant PIV5 viruses expressing foreign genes from numerous pathogens, including influenza, rabies, respiratory syncytial virus, Tuberculosis , Burkholderia , and MERS-CoV have been generated and tested as vaccine candidates preclinically [10–15]. Because it actively replicates in the respiratory tract following intranasal immunization, PIV5-vectored vaccines can generate mucosal immunity that includes antigen-specific IgA antibodies and long-lived IgA plasma cells [12, 16]. Recently a PIV5-vectored vaccine expressing the spike protein from SARS-CoV-2 Wuhan (ancestral strain) (WA1; CVXGA1) has been shown to be efficacious in mice and ferrets [17].…”