Magnitude and Breadth of the Neutralizing Antibody Response in the RV144 and Vax003 HIV-1 Vaccine Efficacy Trials

It is widely believed that a neutralizing antibody (NAb) response of sufficient magnitude, breadth, and duration would be highly beneficial for human immunodeficiency virus type 1 (HIV-1) vaccines [1–3]. Indeed, Nabs protect against experimental challenge with simian human immunodeficiency virus (SHIV) in nonhuman primates [4–6], and they exert strong selective pressure on HIV-1 after infection in humans [7, 8]. Neutralization occurs when antibodies bind to functional envelope glycoprotein (Env) spikes on the virus surface to prevent entry into host cells [9–11]. Each Env spike consists of 3 surface gp120 molecules bound noncovalently to 3 transmembrane gp41 molecules [12, 13]. These glycoproteins exhibit an extraordinary degree of genetic and antigenic variability that poses major challenges for vaccine development [14, 15]. Moreover, the virus uses a number of mechanisms to evade NAbs [7, 12, 16]. As a result, a minor subset of circulating variants exhibit a highly neutralization-sensitive tier 1 phenotype and are often susceptible to vaccine-elicited NAbs, whereas most circulating strains exhibit a less sensitive tier 2 phenotype and have proven difficult to target with vaccines[1, 2, 15]. A recently completed HIV-1 vaccine efficacy trial in Thailand (RV144) showed that priming with a recombinant canarypox vector (vCP1521) and boosting with this vector plus bivalent gp120 protein (AIDSVAX B/E) can provide partial protection against the acquisition of HIV-1 infection in a community-based heterosexual population [17]. The same bivalent gp120 immunogen, when used alone and with an increased number of inoculations (Vax003 trial), showed no protection in a cohort of Thai injection drug users [18]. In addition, no overall protection was seen when a similar regimen of bivalent gp120 (AIDSVAX B/B) was used alone in a cohort of mostly men who have sex with men (MSM) in North America and the Netherlands (Vax004 trial) [19]. 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.