Safety and Immunogenicity of a Recombinant HIV Type 1 Glycoprotein 160 Boosted by a V3 Synthetic Peptide in HIV-Negative Volunteers

Abstract

The safety and the immunogenicity of a recombinant hybrid envelope glycoprotein MN/LAI (rgp160) followed by booster injections of a V3 (MN) linear peptide were evaluated in HIV-negative adults at low risk for HIV infection. Volunteers received either rgp160 in alum at 0, 1, and 6 months (group A), rgp160 at 0 and 1 months followed by V3 at 3 and 6 months formulated in alum (group B), or in Freund's incomplete adjuvant (FIA) (group C). Local and systemic reactions were mild to moderate and resolved within the first 72 hr after immunization. No significant biological changes (routine tests and autoantibodies) were observed. One month after the last injection in either group, neutralizing antibodies (NAs) against the HIV-1 MN isolate were detected in 4 of 5 (A), 7 of 10 (B), and 10 of 10 (C) subjects with significantly higher geometric mean titers in the latter group. Four of nine sera with the highest NA titers against MN weakly cross-neutralized the HIV-1 SF2 isolate; none had NA against the HIV-1 LAI strain or against a North American primary isolate. Specific lymphocyte T cell proliferation to rgp160 was detected in 92% of the subjects after the second injection of rgp160 and in 80% of them 12 months after the first injection. A weak and short-lived envelope-specific CD(4+)-mediated cytotoxic lymphocyte activity was detected at certain time points in few subjects. This prime-boost vaccine approach using rgp160 followed by a V3 peptide was safe in humans, and was able to elicit high levels of neutralizing antibodies and a strong and persistent T cell lymphoproliferative response to rgp160 and to V3. However, the neutralization response was restricted to the homologous HIV-1 strain and little env-specific cytotoxic activity was induced.

Identification of gp120 Regions Targeted by a Highly Potent Neutralizing Antiserum Elicited in a Chimpanzee Inoculated with a Primary Human Immunodeficiency Virus Type 1 Isolate

“…Other studies indicate that vaccinated animals are able to control a virus inoculum in the absence of detectable NAbs (3,10,35,43). In no case has immunization elicited potent, broadly cross-reactive NAbs against primary isolates (1,8,25,38,46,47).…”

Safety and Immunogenicity of a Live Recombinant Canarypox Virus Expressing HIV Type 1 gp120 MN tm/gag/protease LAI (ALVAC-HIV, vCP205) Followed by a p24E-V3 MN Synthetic Peptide (CLTB-36) Administered in Healthy Volunteers at Low Risk for HIV Infection

“…12 In contrast, two or three injections of soluble gp160 MN/LAI in alum or FIA elicited low-level neutralizing responses, but no CTL activity. 13 In addition, priming with the soluble gp160 MN/LAI (alum or FIA) and boosting with a synthetic V3 MN peptide induced high neutralizing antibody titers but still no CTL activity could be detected, 13 emphasizing the essential role of priming with a live recombinant vector for the induction of a CTL response.…”

Restricted Specificity of Anti-V3 Antibodies Induced in Humans by HIV Candidate Vaccines

“…However, none of these sera was able to neutralize the HIV-1 SF2 isolate. 25 Following injection of vCP125 and rgpl60 in Montanide ISA 51, an increased anti-V3 antibody response was observed ( Fig. 1C and D).…”

“…These results were in accordance with previous results showing that 90% of humans immunized by vCP125 and rgpl60 neutralized the homologous HIV-1 strain MN whereas 35% of the vaccinées also developed neutralizing antibodies against the heterologous HIV-1 strain SF2.24 AU vaccinées immunized with rgpl60 and the V3MN synthetic peptide developed homologous neutralizing antibodies, 44% had cross-neutralizing antibodies against the HIV-1 SF2 isolate, and none of them neutralized the HIV-1 IIIB isolate.25 None of the vaccinées developed neutralizing antibodies against a North American HIV-1 primary isolate. 24,25 All sera from macaques, whatever the immunization protocol, reacted with peptides corresponding to SF2 isolate and many also reacted with peptides corresponding to MN, IIIB, and RF isolates. In contrast, sera from guinea pigs reacted with peptides corresponding to MN, RF, and SF2 isolates, but none reacted with the IIIB peptide.…”

“…24,25 The human volunteers were assigned to one of the six following groups belonging to the ANRS trials VAC01, VAC02, and VAC03. In group A, subjects received intramuscularly 105 8 TCID50 (50% tissue culture infectious dose) of ALVAC-HIV (vCP205) at months 0, 1, 3, 6, and 12.28 In group B, volunteers received 176 pg of rgpl60 in alum at months 0,1, and 6 whereas in group E they received rgpl60 in Montanide ISA 51 at months 0 and 1 followed by 200 pg of V3MN peptide in Montanide ISA 51 at months 3 and 6.…”