Immunogenicity of Bivalent Human Papillomavirus DNA Vaccine Using Human Endogenous Retrovirus Envelope-Coated Baculoviral Vectors in Mice and Pigs

Abstract

Human papillomavirus is known to be the major pathogen of cervical cancer. Here, we report the efficacy of a bivalent human papillomavirus type 16 and 18 DNA vaccine system following repeated dosing in mice and pigs using a recombinant baculovirus bearing human endogenous retrovirus envelope protein (AcHERV) as a vector. The intramuscular administration of AcHERV-based HPV16L1 and HPV18L1 DNA vaccines induced antigen-specific serum IgG, vaginal IgA, and neutralizing antibodies to levels comparable to those achieved using the commercially marketed vaccine Cervarix. Similar to Cervarix, AcHERV-based bivalent vaccinations completely blocked subsequent vaginal challenge with HPV type-specific pseudovirions. However, AcHERV-based bivalent vaccinations induced significantly higher cell-mediated immune responses than Cervarix, promoting 4.5- (HPV16L1) and 3.9-(HPV18L1) fold higher interferon-γ production in splenocytes upon stimulation with antigen type-specific pseudovirions. Repeated dosing did not affect the immunogenicity of AcHERV DNA vaccines. Three sequential immunizations with AcHERV-HP18L1 DNA vaccine followed by three repeated dosing with AcHERV-HP16L1 over 11 weeks induced an initial production of anti-HPV18L1 antibody followed by subsequent induction of anti-HPV16L1 antibody. Finally, AcHERV-based bivalent DNA vaccination induced antigen-specific serum IgG immune responses in pigs. These results support the further development of AcHERV as a bivalent human papillomavirus DNA vaccine system for use in preventing the viral infection as well as treating the infected women by inducing both humoral and cell-mediated immune responses. Moreover, the possibility of repeated dosing indicates the utility of AcHERV system for reusable vectors of other viral pathogen vaccines.

Induction of mucosal immunity against pathogens by using recombinant baculoviral vectors: Mechanisms, advantages, and limitations

“…Such BacMam vectors carried genes that coded for L1 capsid proteins from different high-risk HPV types (bivalent and trivalent vectors). 123,[183][184][185] In these reports, animals received 3 doses of rAcMNPV via the i.m. route, rather than the i.n.…”

“…route used for the influenza virus. [183][184][185] In other work, mice were immunized through the sublingual (s.l.) route, which had the same efficacy as the i.m.…”

“…123 Also, pigs were immunized via s.c. route with the BacMam vector, employing a dose ten times higher than in mice, and produced anti-L1 IgG in serum. 185 Mice immunized via i.m. or s.l.…”

Therapeutic potential of an AcHERV-HPV L1 DNA vaccine

“…Previously, we demonstrated that human endogenous retrovirus (HERV) enveloped, replication-deficient baculovirus delivering HPV L1 genes (AcHERV-HPV) induced high levels of humoral and cellular immunity, conferring complete protection against HPV type-specific pseudovirions (Lee et al, 2010(Lee et al, , 2012Cho et al, 2014). Here, we examined whether the trivalent HPV L1 DNA vaccine exhibits antitumor efficacy in a murine model of HPV L1-associated cervical cancer.…”

Diseño racional de una vacuna recombinante contra el virus de la fiebre aftosa vectorizada e inmunomodulada por baculovirus

“…Este tipo de estrategia resultó más eficiente comparada a la inmunización con sus contrapartes de vacunas a DNA debido tanto a la mayor eficiencia de transducción de estos baculovirus pseudotipados como a las mencionadas propiedades adyuvantes de los mismos. Además de la proteína G de VSV, es posible utilizar otras proteínas de superficie como las derivadas de retrovirus endógenos humanos (HERV), con las que se desarrollaron vacunas experimentales bivalentes contra los HPV 16 y 18 [90] o trivalentes 16/18/58 [91].…”