HIV-1 Env DNA prime plus gp120 and gp70-V1V2 boosts induce high level of V1V2-specific IgG and ADCC responses and low level of Env-specific IgA response: implication for improving RV144 vaccine regimen

Dear Editor, According to UNAIDS, 435 million people have died of AIDS, and about 36.7 million people were still living with HIV worldwide by the end of 2015. Therefore, it is essential to develop an efficacious vaccine to prevent HIV infection. However, even with numerous HIV vaccine clinical trials having been completed, no HIV vaccine has successfully emerged.1,2 Notably, the RV144 HIV vaccine regimen, which comprises a recombinant viral vector vaccine ALVAC-HIV (vCP1521) prime and bivalent gp120 vaccine AIDSVAX B/E boost showed an efficacy of 31.2% reduction of HIV-1 infection in clinical trial.2,3 Inspired by these promising results, a large-scale HIV vaccine trial (HVTN 702), based on the RV144 vaccine regimen tested in clinical trials in Thailand, will be launched in South Africa.4 Studies on the RV144 vaccine regimen revealed that this vaccine does not induce effective neutralizing antibody responses, but it does elicit antibody-dependent cell cytotoxicity (ADCC) effect, which may play a key role in preventing HIV infection. It was demonstrated that the protection against HIV-1 infection was directly correlated with the level of IgG specific for the HIV-1 gp120 V1V2 region (V1V2-specific IgG, V1V2-IgG) and inversely with the level of IgA specific for HIV-1 envelope protein (Env-specific IgA, Env-IgA) in vaccine recipients.5 These results suggest that V1V2-IgG, Env-IgA and ADCC6 may be important parameters associated with the protective effect induced by RV144 vaccine and that a more effective and safe HIV vaccine regimen could be designed and developed on the basis of these parameters. We previously designed an effective and safe subunit vaccine candidate against Middle East respiratory syndrome coronavirus by using an immunofocusing strategy, that is, identifying the shortest fragment in Middle East respiratory syndrome coronavirus spike protein containing the critical epitopes that induce protective immune responses, while eliminating the fragment(s) with epitopes that may elicit non-protective or harmful immune responses.7 Here we applied this immunofocusing strategy to design a DNA prime/protein boost vaccine regimen. To induce immune response focusing on V1V2 region in gp120, additional boosts with gp70-V1V2 that contains the V1V2 region was applied after the primes with HIV-1 Env-coding DNA (pEnv) and boosts with HIV-1 gp120 (Figure 1A). Two groups of New Zealand rabbits (n= 3, 6–8 weeks of age, ~ 2 kg) were intradermally immunized with the following vaccine regimens, respectively (Figure 1A): (1) Prime three times with a plasmid encoding HIV-1 JRFL Env with gp41 cytoplasmic domain truncated (pEnv) and boost twice with gp120, as well as boost twice with gp70-V1V2 of the HIV-1 JRFL (pEnv+gp120+gp70-V1V2). Both gp120 and gp70-V1V2, which were expressed in 293 T cells, were obtained from Jiangsu Haiyuan Company, Taizhou, China. (2) Prime three times with pEnv and boost four times with gp120 (pEnv +gp120). The gp70-V1V2 is mainly composed of V1V2 region (residues 157–196, according to HXB2 sequence number) in gp120 and sequences at the two ends that can form a scaffold structure to stabilize its conformation, which has been clinically used to detect antibodies against V1V2.5,8 Four additional groups of New Zealand rabbits were intradermally immunized with the following vaccine regimens, respectively, as controls: (1) prime three times with pEnv and boost four times with gp70-V1V2 (pEnv+gp70-V1V2); (2) prime once and boost four times with gp120 (gp120); (3) prime once and boost four times with gp70-V1V2 (gp70-V1V2), and (4) prime once and boost four times with phosphate-buffered saline (PBS) (Figure 1A). To evaluate the efficacy of the above vaccine regimens to induce V1V2-IgG, rabbit sera from different immunization groups were collected 10 days after the last boost for testing the titers of the antisera to bind gp70-V1V2. As shown in Figure 1B, the gp70-V1V2 and pEnv+gp70-V1V2 groups exhibited the highest titer of antibody responses, followed by the pEnv+gp120+gp70-V1V2 group and then