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Studies Shed Light on Immune Responses in HIV Vaccine Trials

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A specific type of antibody known as IgG3, targeting the V1V2 portion of the HIV envelope, appears to be responsible for the temporary protection against HIV infection seen in one of the only partially successful HIV vaccine trials to date, according to 2 reports in the March 19 edition of Science Translational Medicine.

Many experts believe the global HIV/AIDS pandemic cannot be ended without at least a partially effective HIV vaccine, but so far most vaccine trials have produced disappointing results. However, in 2009 investigators announced that a prime-boost combination of 2 vaccines -- ALVAC-HIV and AIDSVAX --demonstrated modest efficacy in a clinical trial known as RV144, which included more than 16,000 participants in Thailand.

The new studies, by 2 independent laboratories, both found that only a single subclass of V1V2-directed immunoglobulin G antibodies -- the IgG3 subclass -- was associated with antiviral responses linked to the reduced risk of HIV infection seen in RV144, according to a press release issued by the U.S. National Institute of Allergy and Infectious Diseases, which partially funded the research.

The first study, by Galit Alter of the Ragon Institute and colleagues, showed that the RV144 vaccine combination induced antibodies able to direct multiple coordinated HIV-eliminating responses, and that V1V2-specific IgG3 antibodies were primarily responsible. A strategy using repeated doses of the AIDSVAXvaccine alone in the VAX003 trial did not produce this kind of response. Only the combination tested in RV144 induced IgG1 and IgG3 antibodies targeting the crown of the HIV envelope V2 loop, according to the researchers.

In the second study, by Georgia Tomaras of the Duke Human Vaccine Institute and colleagues, the researchers also found that V1V2-specific IgG3 antibodies correlated with decreased risk of infection in RV144 vaccine recipients, and were linked to anti-HIVactivity. They further reported that blood levels of V1V2-specific IgG3 antibodies decreased rapidly -- as did the efficacy of the vaccines tested in RV144, from 60% at 12 months to 31% at 42 months post-vaccination.

"More is not always better with an antibody response," Tomaras said in a Duke Medicine press release. "Instead, it’s the underlying quality of the immune response. Going forward with other vaccine trials, it will be important to know the subclass, specificity, and antiviral functions of antibodies that are induced."

"Taken together, these results suggest that IgG3 might be the key difference between the efficacy outcomes of the VAX003 and RV144 HIV vaccine trials," said Col. Jerome Kim of the U.S. Military HIV Research Program, a co-author of both reports. "We now know more about the attributes of the antibodies that may play a role in reducing the risk of HIV infection."

3/25/14

References

AW Chung, M Ghebremichael, H Robinson, G Alter, et al. Polyfunctional Fc-Effector Profiles Mediated by IgG Subclass Selection Distinguish RV144 and VAX003 Vaccines. Science Translational Medicine 6(228):228ra38. March 19, 2014.

NL Yates, H-X Liao, Y Fong, G Tomaras, et al. Vaccine-Induced Env V1-V2 IgG3 Correlates with Lower HIV-1 Infection Risk and Declines Soon After Vaccination. Science Translational Medicine 6(228):228ra39. March 19, 2014.

Other Sources

U.S. National Institute of Allergy and Infectious Diseases. NIH Grantees Sharpen Understanding of Antibodies that May Cut Risk of HIV Infection. NIH News press release. March 19, 2014.

U.S. Military HIV Research Program. New Studies Enhance Knowledge of Antibodies in HIV Vaccine Trials. Press release. March 19, 2014.

Duke Medicine. Past HIV Vaccine Trials Reveal New Path to Success. Press release. March 19, 2014.