Immunogenicity of Recombinant Adenovirus-Human Immunodeficiency Virus Vaccines in Chimpanzees Following Intranasal Administration

Abstract

Recombinant adenovirus (Ad)-human immunodeficiency virus (HIV) vaccines expressing HIVIIIB Env and Gag proteins were evaluated for immunogenicity in chimpanzees following intranasal administration. When Ad7-, Ad4-, and Ad5-vectored vaccines were administered sequentially at 0, 24, and 52 weeks, respectively, to three chimpanzees, the inoculations resulted in limited virus replication in the nasopharynx, but extensive Ad-HIV replication occurred in the intestine. High-titered IgG serum antibody responses to Env and Gag that were nonneutralizing were induced following booster administration of Ad4-HIV recombinant viruses. Following the Ad5-HIV booster, low levels of neutralizing antibodies as well as V3 loop antibodies were induced in all three chimpanzees that persisted for several months. Administration of a gp160 subunit vaccine (baculovirus derived) in SAF-m 24 weeks later boosted broadly neutralizing serum antibodies that peaked within 1 month of the injection. Two additional subunit boosters 19 and 37 weeks later were progressively less effective at stimulating serum neutralizing antibody responses. Substantial local immune responses were induced in nasal, vaginal, and salivary secretions following the third Ad-HIV intranasal immunization. These responses were further boosted with the gp160 subunit vaccine, which also stimulated production of rectal antibodies. The predominant responses in all secretions tested were of the IgG isotype, although some IgA responses were also detected. Strong blastogenic responses to HIV recombinant Env and Gag proteins were induced after each immunization.

Replicating adenovirus vector prime/protein boost strategies for HIV vaccine development

“…Intratracheal immunization of dogs with recombinant Ad4, 5 and 7 expressing HIV env resulted in enhanced, functional anti-Env antibodies with neutralizing activity [76]. Later the intranasal route compared to oral was found to give the highest level of vector replication in chimpanzees [77], paving the way for vaccine studies in this animal model. Subsequently, intranasal priming with replicating Ad-HIV MN env recombinants and boosting with HIV-1 SF2 gp120 envelope protein [78] were shown to protect 4 of 4 chimpanzees against a low-dose HIV-1 challenge, and 3 of 4 against a high-dose challenge administered one year later with no intervening immunization.…”

Evidence of partial protection against foot-and-mouth disease in cattle immunized with a recombinant adenovirus vector expressing the precursor polypeptide (P1) of foot-and-mouth disease virus capsid proteins.

“…One strategy to present foreign antigens in a replicative form is the use of recombinant viral vectors. Recombinant adenoviruses have been shown recently to be an efficient system for the expression and presentation of foreign antigens and to elicit potent humoral, both systemic and mucosal, and cellular immune responses in humans (Gaydos & Gaydos, 1995) as well as in a number of animal hosts Gallichan et al, 1995 ;Gaydos & Gaydos, 1995 ;Hsu et al, 1994 ;Kadoi, 1997 ;Lubeck et al, 1994 ;Mittal et al, 1996 ;Randrianarison-Jewtoukoff & Perricaudet, 1995 ;Torres et al, 1995 ;Xiang et al, 1996).…”

Experimental infections of humans with wild-type adenoviruses and with replication-competent adenovirus vectors: replication, safety, and transmission

“…Intranasal administration of recombinant Ad4, Ad5, and Ad7 vaccines to chimpanzees resulted in no signs of respiratory or enteric illness despite evidence for Ad replication (virus recovered in stool and development of anti-Ad neutralizing antibodies). 36 Another investigation found similar results 37 suggesting that these vaccine viruses are safe and do not cause overt illness in chimpanzees even though active replication in the gut occurs.…”