Optimized Mucosal Modified Vaccinia Virus Ankara Prime/Soluble gp120 Boost HIV Vaccination Regimen Induces Antibody Responses Similar to Those of an Intramuscular Regimen

Abstract

The benefits of mucosal vaccines over injected vaccines are difficult to ascertain, since mucosally administered vaccines often induce serum antibody responses of lower magnitude than those induced by injected vaccines. This study aimed to determine if mucosal vaccination using a modified vaccinia virus Ankara expressing human immunodeficiency virus type 1 (HIV-1) gp120 (MVAgp120) prime and a HIV-1 gp120 protein boost could be optimized to induce serum antibody responses similar to those induced by an intramuscularly (i.m.) administered MVAgp120 prime/gp120 boost to allow comparison of an i.m. immunization regimen to a mucosal vaccination regimen for the ability to protect against a low-dose rectal simian-human immunodeficiency virus (SHIV) challenge. A 3-fold higher antigen dose was required for intranasal (i.n.) immunization with gp120 to induce serum anti-gp120 IgG responses not significantly different than those induced by i.m. immunization. gp120 fused to the adenovirus type 2 fiber binding domain (gp120-Ad2F), a mucosal targeting ligand, exhibited enhanced i.n. immunogenicity compared to gp120. MVAgp120 was more immunogenic after i.n. delivery than after gastric or rectal delivery. Using these optimized vaccines, an i.n. MVAgp120 prime/ combined i.m. (gp120) and i.n. (gp120-Ad2F) boost regimen (i.n./i.m.-plus-i.n.) induced serum anti-gp120 antibody titers similar to those induced by the intramuscular prime/ boost regimen (i.m./i.m.) in rabbits and nonhuman primates. Despite the induction of similar systemic anti-HIV-1 antibody responses, neither the i.m./i.m. nor the i.n./i.m.-plusi.n. regimen protected against a repeated low-dose rectal SHIV challenge. These results demonstrate that immunization regimens utilizing the i.n. route are able to induce serum antigen-specific antibody responses similar to those induced by systemic immunization.IMPORTANCE Mucosal vaccination is proposed as a method of immunization able to induce protection against mucosal pathogens that is superior to protection provided by parenteral immunization. However, mucosal vaccination often induces serum antigen-specific immune responses of lower magnitude than those induced by parenteral immunization, making the comparison of mucosal and parenteral immunization difficult. We identified vaccine parameters that allowed an immunization Citation Jones DI, Pollara JJ, Johnson-Weaver BT, LaBranche CC, Montefiori DC, Pickup DJ, Permar SR, Abraham SN, Maddaloni M, Pascual DW, Staats HF. 2019. Optimized mucosal modified vaccinia virus Ankara prime/soluble gp120 boost HIV vaccination regimen induces antibody responses similar to those of an intramuscular regimen. J Virol 93:e00475-19.

Nasal Immunization With Small Molecule Mast Cell Activators Enhance Immunity to Co-Administered Subunit Immunogens

“…However, we selected a low antigen dose in our vaccine studies to increase the sensitivity of evaluating the adjuvant activity of our MCA small molecules. The antigen dose delivered intranasally in this study is lower than the antigen dose used by others in parenteral WNV vaccine studies (77,78) and we also reported that nasal immunization may require at least three times more antigen as parenteral immunization to induce a similar immune response (21). The vaccine conditions evaluated in this proof-of-concept study may not be optimal for induction of protective immunity against West Nile Virus; however, this study provides a foundation for further evaluation of mast cell activator small molecules as adjuvants for mucosal delivery.…”

“…The results from this study provide the support that MCAs are a new class of vaccine adjuvants for mucosal immunization. Mast cell activating polymeric compounds (5,13), peptides (21,22), and now, small molecules have been shown to enhance vaccine-specific immunity after nasal delivery. The hydrophobic nature of small molecules will require optimal formulations or medicinal chemical modifications to maximize compound activity and advance these compounds through the lead optimization phase of drug discovery.…”

“…Vaccination with mast cell activating peptides, such as Mastoparan 7 (M7) that are synthesized with high purity, may reduce variability in host immune responses. M7 is a highly active analog (20) of the peptide mastoparan and provides potent adjuvant activity after nasal immunization (21,22). Nasal immunization with M7 and a cocaine-hapten-conjugate vaccine provided effective adjuvant activity and reduced the effects of cocaine-induced locomotion in mice (22).…”

“…Nasal immunization with M7 and a cocaine-hapten-conjugate vaccine provided effective adjuvant activity and reduced the effects of cocaine-induced locomotion in mice (22). M7 is also a potent mucosal vaccine adjuvant in mice, rabbits, and non-human primates and enhanced antigenspecific immunity when combined with an HIV immunogen (21). Although M7 is an effective mucosal vaccine adjuvant, small molecule mast cell activators may be an additional mast cell activating adjuvant and provide a cost-efficient vaccine adjuvant that would be suitable for future clinical use.…”

Novel mucosal adjuvant, mastoparan-7, improves cocaine vaccine efficacy

“…The potency of the nasal adjuvant activity of M7 agrees with recent results from our laboratory where M7 was used as a nasal vaccine adjuvant for HIV-1 gp120 in mice, rabbits and non-human primates. 29 Due to the common practice of administering cocaine to mucosal surfaces, the ability to promote strong, specific IgA responses against cocaine is a key advantage of a mucosal vaccine strategy and has the potential to more effectively neutralize cocaine that is administered via the nasal or oral mucosae. 4 Future studies may be required to evaluate Fig.…”