Magnitude and Breadth of a Nonprotective Neutralizing Antibody Response in an Efficacy Trial of a Candidate HIV-1 gp120 Vaccine

Vaccine Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 08/2010; 202(4):595-605. DOI: 10.1086/654816
Source: PubMed


A candidate vaccine consisting of human immunodeficiency virus type 1 (HIV-1) subunit gp120 protein was found previously to be nonprotective in an efficacy trial (Vax004) despite strong antibody responses against the vaccine antigens. Here we assessed the magnitude and breadth of neutralizing antibody responses in Vax004.
Neutralizing antibodies were measured against highly sensitive (tier 1) and moderately sensitive (tier 2) strains of HIV-1 subtype B in 2 independent assays. Vaccine recipients were stratified by sex, race, and high versus low behavioral risk of HIV-1 acquisition.
Most vaccine recipients mounted potent neutralizing antibody responses against HIV-1(MN) and other tier 1 viruses. Occasional weak neutralizing activity was detected against tier 2 viruses. The response against tier 1 and tier 2 viruses was significantly stronger in women than in men. Race and behavioral risk of HIV-1 acquisition had no significant effect on the response. Prior vaccination had little effect on the neutralizing antibody response that arose after infection.
Weak overall neutralizing antibody responses against tier 2 viruses is consistent with a lack of protection in this trial. The magnitude and breadth of neutralization reported here should be useful for identifying improved vaccines.

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Available from: David C Montefiori, Apr 11, 2014
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    • "However, similar to previous human immunizations with envelope monomers or trimmers, no (broadly) neutralizing antibodies were induced. In the best of the cases, earlier studies showed vaccine-induced antibodies able to neutralize easily neutralizable viral isolates or the vaccine strain only [18-21]. These limitations highlight the need for the design of novel immunogens to elicit broadly neutralizing antibodies, although difficulties related to masked epitopes or tolerance mechanisms induced by self-homologies, among others, remain [22-24]. "
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    Journal of Translational Medicine 02/2013; 11(1):48. DOI:10.1186/1479-5876-11-48 · 3.93 Impact Factor
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    • "postulated to induce neutralizing antibodies (Flynn et al., 2005; Pitisuttithum et al., 2006; Gilbert et al., 2010), the prospects for a neutralizing antisera-inducing HIV vaccine appeared bleak and there was a shift within the HIV prevention field toward vaccines designed to induce mainly T cell responses, as previously reviewed (Barouch, 2010; McElrath and Haynes, 2010; Pantaleo et al., 2010; Picker et al., 2012). "
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    ABSTRACT: Most neutralizing antibodies act at the earliest steps of viral infection and block interaction of the virus with cellular receptors to prevent entry into host cells. The inability to induce neutralizing antibodies to HIV has been a major obstacle to HIV vaccine research since the early days of the epidemic. However, in the past three years, the definition of a neutralizing antibody against HIV has been revolutionized by the isolation of extremely broad and potent neutralizing antibodies from HIV-infected individuals. Considerable hurdles remain for inducing neutralizing antibodies to a protective level after immunization. Meanwhile, novel technologies to bypass the induction of antibodies are being explored to provide prophylactic antibody-based interventions. This review addresses the challenge of inducing HIV neutralizing antibodies upon immunization and considers notable recent advances in the field. A greater understanding of the successes and failures for inducing a neutralizing response upon immunization is required to accelerate the development of an effective HIV vaccine.
    Journal of Experimental Medicine 02/2013; 210(2):209-23. DOI:10.1084/jem.20121827 · 12.52 Impact Factor
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    • "The gp120 protein component in all 3 clinical trials was designed to elicit NAbs [20, 21]. In Vax004, strong NAb responses were seen against a subset of tier 1 viruses, and sporadic weak responses were seen against tier 2 viruses [22]. Here we assessed the magnitude and breadth of NAb responses in RV144 and Vax003. "
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    The Journal of Infectious Diseases 05/2012; 206(3):431-41. DOI:10.1093/infdis/jis367 · 6.00 Impact Factor
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