Article

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: 5.78). 08/2010; 202(4):595-605. DOI: 10.1086/654816
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: David C Montefiori, Apr 11, 2014
0 Followers
 · 
161 Views
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 13.91 Impact Factor
  • Source
    • "Statistical analysis of the sequential viral load was carried out by aligning the starting week of infection for each macaque in a group, to account for different times of infection following repeated doses of virus challenge. The AUC was used for the absorbance of all serially diluted serum antibody titrations (Gilbert et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetic, epidemiological and experimental evidence suggest that the major histocompatibility complex (MHC) is critical in controlling human immunodeficiency virus (HIV) infection. The objectives of this study were to determine whether novel recombinant Mamu MHC constructs would elicit protection against rectal challenge with heterologous simian-human immunodeficiency virus (SHIV) strain SF162.P4 in rhesus macaques. Mamu class I and II gene products were linked together with HIV gp140, simian immunodeficiency virus (SIV) p27 and heat-shock protein 70 to dextran. The vaccine was administered to two groups, each consisting of nine macaques, either subcutaneously (SC), or rectally and boosted by SC immunization. The controls were untreated or adjuvant-treated animals. Repetitive rectal challenges with up to ten doses of SHIV SF162.P4 showed a significant decrease in the peak and sequential viral RNA concentrations, and three macaques remained uninfected, in the nine SC-immunized animals, compared with infection in all nine controls. Macaques immunized rectally followed by SC boosters showed a less significant decrease in both sequential and peak viral loads compared with the SC-immunized animals, and all were infected following rectal challenge with SHIV SF162.P4. Plasma and mucosal IgG and IgA antibodies to Mamu class I alleles and HIV gp120, as well as to RANTES (regulated upon activation, normal T-cell expressed, and secreted; CCR5) were increased, and showed significant inverse correlations with the peak viral load. These results suggested that allo-immunization with recombinant MHC constructs linked to HIV-SIV antigens merits further investigation in preventing HIV-1 infection.
    Journal of General Virology 04/2012; 93(Pt 7):1506-18. DOI:10.1099/vir.0.041061-0 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The explosive proliferation of battery-powered equipment in the past decade has accelerated the development and usage of Low-Dropout voltage regulators (sometimes referred to as PNP voltage regulators). Compared to the standard NPN regulator, the Low-Dropout Regulator (LDO) can hold its output voltage in regulation with much less voltage across it: the NPN requires about 2 V of “headroom” to regulate, while the LDO will typically work with less than 500 mV of input-to-output voltage differential. The reduced input voltage requirement of an LDO is advantageous in battery-powered systems, since it translates directly into fewer battery cells, less wasted power, smaller size, and lower cost. The LDO's higher level of performance requires the use of external compensation capacitors, something an NPN regulator does not need. Also, the capacitors must be carefully selected for electrical parameters to assure stability. This article will develop an overview of LDO/NPN regulator theory, focusing on loop compensation and the parameters affecting regulator stability
    Wescon/97. Conference Proceedings; 12/1997
Show more