We assessed the NAb response in 2 HIV-1 vaccine efficacy trials in which either partial protection (RV144) [17
] or no protection (Vax003) [18
] was seen. By all measures, the peak NAb response in RV144 was substantially weaker than the peak response in Vax003. Only tier 1 viruses were neutralized in RV144, as mediated in part by Abs against the V3 loop of gp120. Weak neutralization of tier 2 viruses was occasionally seen in Vax003, but only in the more sensitive A3R5 assay. Peak responses in both trials waned considerably after 6 months, possibly reflecting a rate of decay for other antibody responses as well and suggesting that regular boosting will be required to maintain adequate titers.
After initial waning, low titers of NAbs persisted in a subset of RV144 vaccine recipients for at least 3 years. This observation, together with the isolation of neutralizing mAbs CH21, CH22, and CH23 from circulating memory B cells, suggest that the RV144 vaccine is able to induce, at least in a subset of vaccine recipients, long-term memory responses through both memory B cells and long-lived plasma cells. An earlier study of recombinant canarypox prime/gp120 protein boosting showed that low titers of NAbs can persist for at least 4–5 years and that recall of peak titers is possible by boosting again with gp120 protein [38
A priming effect was seen for vCP1521 in that the peak NAb response after final boosting in RV144 (2 gp120 inoculations) was stronger than the response seen after 2 gp120 protein inoculations alone in Vax003 (Figure ). Priming was relatively weak as compared to that for another canarypox vector, vCP1452, which required only a single protein boost for strong NAb response [39
]. RV144 (vCP1521) and the trials that tested vCP1452 used the same schedule of 2 vector inoculations followed by 2 boosts with vector plus gp120 protein. Moreover, they used the same protein dose and adjuvant for bivalent gp120. Multiple reasons might explain the weaker priming in RV144, including a lower dose of vector, different Envs in the vectors and as protein boosts, and the presence of vaccinia virus E3L and K3L genes in vCP1452.
Several HIV-1 vaccine concepts have been tested for efficacy in human trials. One concept tested a vectored Gag-Pol-Nef immunogen that, despite robust virus-specific CD8+
T-cell responses, failed to protect in a predominantly MSM risk group [41
]. The Vax003 and Vax004 trials tested bivalent gp120 proteins that elicited high titers of Env binding antibodies but failed to protect when administered to injection drug users and MSM, respectively [18
]. In Vax004, robust NAbs responses were seen against a subset of tier 1 viruses, with occasional weak neutralization seen against tier 2 viruses [22
]. The response in Vax004 was much stronger than the response in RV144 and was similar to the response in Vax003, with the exception that occasional neutralization of tier 2 viruses in the more stringent TZM-bl assay was only seen in Vax004 [22
RV144 is the first efficacy trial of a vector prime/gp120 protein boost vaccine for HIV-1. It is also the only trial to date in a heterosexual risk group and in which some level of protection was seen. That the NAb response in RV144 was weaker than the responses in Vax003 and Vax004 raises the question of whether NAbs might be sufficient but not necessary for prevention of HIV-1 infection. Our studies did not address other potentially protective antibody activities, such as Fc receptor–mediated effector functions [43
] and antibodies that impede virus transmission across intact mucosa [46
]. One Fc receptor–mediated function, antibody-dependent cell mediated cytotoxicity, was detected in a majority of vaccine recipients in RV135 [49
]. It is also possible that NAbs were present in RV144 that were below the level of detection in our assays (eg, ID50
titers of <1:20). Low levels of NAbs might have a greater impact on heterosexual transmission in RV144 than in the higher-risk groups that participated in Vax003 and Vax004. Lower-risk behavior has been associated with lower multiplicity of transmitted/founder viruses [50
] and therefore might be more easily countered by antibodies. The efficacy seen in RV144 might be improved by eliciting stronger NAb responses, particularly against tier 2 viruses, and/or by maintaining peak antibody responses for longer periods. Detailed studies of NAbs and other potential antiviral antibody activities in future clinical trials may provide new insights into the requirements for vaccine-mediated protection against HIV-1.