Inducing the “Right Antibodies” to Protect Against HIV Infection

To date, only one clinical trial of an HIV vaccine has resulted in a marginal but statistically significant reduction in the rate of HIV infection.  The only independent variable identified as a correlate of reduced risk in this trial--RV144, conducted in Thailand between 2006 and 2009 1--was the presence of elevated levels of antibodies (Abs) to the V1V2 region of the gp120 glycoprotein 2,3.  Perhaps because of the unexpected correlation with a variable region of the envelope protein and the fact that these Abs do not neutralize the virus but apparently mediate their anti-viral effects via Fc-mediated functions, there has been a paucity of work on HIV vaccines for human use building on this signal of protection from human data. During the intervening years since the publication of these findings, several reports have been published showing that, similar to the findings in humans, V2 Abs correlate with protection from SIV in non-human primates (NHPs) 4. Importantly, V2 Abs are a correlate, and not necessarily mediators of protection; nonetheless, the repeated finding of elevated levels of V2 Abs in human and NHPs who have successfully repulsed or controlled infection merits much more extensive investigation.

Subsequent to the RV144 trial, the HIV vaccine field has focused on developing vaccine constructs as proteins, DNAs, recombinant viruses, and mRNAs that present the whole envelope in various trimolecular configurations.  In parallel, extensive studies have illuminated the lineage of B cells producing broadly neutralizing Abs and have attempted to guide the humoral immune response using a multitude of vaccine constructs to sequentially stimulate cells with relevant germline genes through a series of maturation steps to the generation and expression of broadly neutralizing Abs.  These latter studies are characterized by elegant science but have not yet achieved the goal of protecting NHPs or humans from SIV, SHIV or HIV.  Notably, neither of these approaches has succeeded in inducing either the levels of V1V2 Abs that were associated with reduced infection in the RV144 trial or broadly neutralizing Abs.

The origin of the paper currently published in Nature Communications, “Differential V2-directed Antibody Responses in Non-human Primates Infected with SHIVs or Immunized with Diverse HIV Vaccines”, was the publication of the RV144 data 2,3.  At that time, our lab embarked on a series of experiments based on the hypotheses that (a) vaccines could be designed that would focus the humoral immune response on V2 and induce Abs of the type that were correlated with reduced HIV infection, and (b) V2 Abs play a role in protection from HIV infection.  To date, we have published a series of studies which support the first of these two hypotheses.  Thus, structural studies of human anti-V2 monoclonal Abs identified different types of V2 epitopes 5,6; protein design techniques were used to develop and synthesize V2-protein scaffold immunogens carrying these epitopes 7,8; these immunogens were then tested for antigenicity in vitro and for immunogenicity in vivo in rabbits 5,9 and subsequently in NHPs 9-11.  Our current paper presents the latest data from the studies of our V2 immunogens in NHPs and compares them to the Ab responses of NHPs infected with SHIV or immunized with whole envelope vaccines.

In contrast to the weak and sporadic V2 Ab response of SHIV-infected non-vaccinated NHPs, a strong V2 Ab response was seen in NHPs after immunization with a V2-targeting vaccine protocol. The V2-focused vaccination was superior not only to natural infection but also to immunization with whole Env constructs for inducing functional V2 -specific responses. Strikingly, levels of V2-directed Abs correlated inversely with Abs specific for gp120 and peptides of V3 and C5, demonstrating that a V1V2-targeting vaccine has advantages over the imprecise targeting of SIV/SHIV infections and of whole Env-based immunization regimens for inducing a more focused functional V2-specific Ab response.

Having shown that the V2-scaffold immunogens can induce the types of V2 Abs that were found in the RV144 vaccine recipients, our second hypothesis needs to be tested, i.e., that V2 Abs contribute to protection. Data published recently suggest that V2 Abs may indeed play a role in protection from SHIV in NHPs:  in a challenge study of nine immunized with gp120 DNA and three V1V2-scaffold protein immunogens, four of nine NHPs (p=0.0497) showed an absence of plasma vRNA, cell-associated vDNA in PBMCs, and lymphoid-associated virus over a nine-week period following the final challenge dose with a heterologous Tier 1 SHIV 12.  In this study, the V2 responses did not differ in the tight controllers compared with the non-controllers, indicating that additional studies of the role of the V2 Abs are needed.

            The failure of all Phase 3 HIV vaccine trials except RV144 to reduce the rate of HIV infection puts into sharp relief the need to support NHP and human studies of several vaccine approaches and platforms. This imperative is underscored by the successes of the many different vaccine approaches and platforms for COVID-19, including the mRNA platform which was considered an outlier approach before 2020.  With COVID-19, natural infection induced the “right Abs”, and vaccine development for SARS-CoV-2 followed the lessons from natural infection, i.e., inducing neutralizing Abs against the Spike. The challenge with HIV is much greater; the trick is not how to induce Abs, but how to induce the “right Abs” given a highly complex, mutation-prone, conformationally- and glycan-masked Envelope protein with key epitopes such as those in V2 being poorly immunogenic.  The data summarized in our newly published paper, in which V2-scaffold recombinant proteins preferentially induce V2 Abs, supports the potential utility of this approach and these immunogens for HIV vaccine development.  Active support by funding agencies and foundations to test our approach and many other novel vaccines that may be considered novel, high-risk outliers is urgently needed.


Susan Zolla-Pazner, Ph. D., Departments of Medicine and Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA





  1. Rerks-Ngarm, S. et al. Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand. N Engl J Med 361, 2209-2220 (2009).
  2. Haynes, B. F. et al. Immune Correlates Analysis of the ALVAC-AIDSVAX HIV-1 Vaccine Efficacy Trial. N Engl J Med 366, 1275-1286 (2012).
  3. Zolla-Pazner, S. et al. Vaccine-induced IgG Antibodies to V1V2 Regions of Multiple HIV-1 Subtypes Correlate with Decreased Risk of HIV-1 Infection. Plos One 9, e87572 (2014).
  4. Zolla-Pazner, S., Alvarez, R., Kong, X. P. & Weiss, S. Vaccine-induced V1V2-specific antibodies control and or protect against infection with HIV, SIV and SHIV. Curr Opin HIV AIDS 14, 309-317 (2019).
  5. Jiang, X., Totrov, M., Li, W., Sampson, J. M., Williams, C., et al. Rationally Designed Immunogens Targeting HIV-1 gp120 V1V2 Induce Distinct Conformation-Specific Antibody Responses in Rabbits, J Virol. 90, 11007-11019 (2016).
  6. Wibmer, C. K., Richardson, S. I. Yolitz, J., Cicala, et al. Common helical V1V2 conformations of HIV-1 Envelope expose the α4β7 binding site on intact virions. Nat. Comm., 9, 4489-14 (2018).
  7. Totrov, M., Dash, C. Estimated secondary structure propensities within V1/V2 region of HIV gp120 are an important global antibody neutralization sensitivity determinant. PloS ONE. 9, e94002-e94002 (2014).
  8. Zolla-Pazner, S., Powell, R., Yahyaei, S., Williams, C., et al. Rationally Designed Vaccines Targeting the V2 Region of HIV-1 gp120 Induce a Focused, Cross-Clade-Reactive, Biologically Functional Antibody Response. J. Virol., 90, 10993-11006 (2016).
  9. Hessell, A. J., Powell, R., Jiang, X., Luo, C., et al. Multimeric Epitope-Scaffold HIV Vaccines Target V1V2 and Differentially Tune Polyfunctional Antibody Responses. Cell Rep. 28, 877-895.e6 (2019).
  10. Powell, R. L., Weiss, S., Fox, A., Liu, X., et al. An HIV Vaccine Targeting the V2 Region of the HIV Envelope Induces a Highly Durable Polyfunctional Fc-Mediated Antibody Response in Rhesus Macaques. J Virol. 94, e01175-20 (2020).
  11. Devasundaram, S., Rosati, M., Valentin, A., Weiss, S., et al. Priming with DNA Expressing Trimeric HIV V1V2 Alters the Immune Hierarchy Favoring the Development of V2-Specific Antibodies in Rhesus Macaques. J Virol. 95, e01193-20 (2020).
  12. Hessell, A. J., Li L., Malherbe, D.C., Barnette, P., et al. Virus Control in Vaccinated Rhesus Macaques Is Associated with Neutralizing and Capturing Antibodies against the SHIV Challenge Virus but Not with V1V2 Vaccine-Induced Anti-V2 Antibodies Alone. J Immunol. 206:1266-1283 (2021).