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April 25, 2013

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QUESTIONS AND ANSWERS
The HVTN 505 HIV Vaccine Regimen Study


(Note: This Q&A was originally posted on Aug. 24, 2009, and updated on April 25, 2013)

see Statement

1.  What is the HVTN 505 study?

The HVTN 505 study is a Phase IIb exploratory clinical trial examining an investigational HIV vaccine regimen. When launched in 2009, the study’s main goal was to test whether the vaccine regimen could reduce the amount of HIV in the blood (viral load) of vaccinated people who later became infected with the virus. The study also was designed to generate additional information about the vaccine regimen’s safety, which previous studies had shown to be good.

In August 2011, the scope of the study’s primary goals was expanded to include an investigation of whether the experimental vaccine regimen could also prevent HIV infection. This was done to allow for closer examination of the immune responses generated by the vaccine regimen to explore similarities with those generated by the vaccine tested in the RV 144 HIV vaccine study in Thailand. The trial was also expanded in light of animal research that found that the HVTN 505 vaccine regimen prevented infection with simian immunodeficiency virus (the monkey equivalent of HIV) 50 percent of the time among two-thirds of the nonhuman primates tested.

The study was not intended to lead to the licensure of the vaccine regimen being tested, but rather to answer important scientific questions that could lead to the discovery and development of new and improved HIV vaccines in the future.

During a scheduled interim review of the study’s data on April 22, 2013, an independent data and safety monitoring board (DSMB) found that the vaccine regimen did not prevent HIV infection nor reduce viral load among vaccine recipients who became infected with HIV. As a result, the DSMB recommended that no further vaccinations with the investigational regimen be administered. NIAID concurred with this recommendation. For further discussion of these findings and their implications, please see questions 8, 9 and 11 below.

2. Who sponsored and conducted this study?
 

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, sponsored the HVTN 505 study. The NIAID-supported HIV Vaccine Trials Network (HVTN) conducted the clinical trial. NIAID’s Dale and Betty Bumpers Vaccine Research Center (VRC) developed the two investigational vaccines that were being studied.

The study was led by co-chairs Scott M. Hammer, M.D., professor of medicine and chief, division of infectious diseases at Columbia University Medical Center, New York, and Magdalena Sobieszczyk, M.D., assistant professor of clinical medicine at Columbia University Medical Center.

3. What vaccine regimen was tested in the HVTN 505 study?
 

HVTN 505 evaluated two different vaccines in a prime-boost strategy where one vaccine was designed to prime the immune system and another vaccine was designed to boost the immune response. This type of strategy generally induces different types of immune system responses compared with vaccine regimens in which only one type of vaccine is administered.

The HVTN 505 vaccine regimen consisted of a series of three immunizations over the course of eight weeks with a recombinant DNA-based vaccine (the priming vaccine). The DNA priming vaccine (called VRC-HIVDNA016-00-VP) contained genetic material expressing antigens representing proteins from both the surface and internal structures of HIV. Following completion of the series of three immunizations with the priming vaccine, vaccine recipients received a single immunization in week 24 with a recombinant vaccine (the boosting vaccine) based on a weakened adenovirus type 5 (Ad5) to carry the genetic material expressing a matching set of HIV antigens to stimulate the immune system. Adenoviruses are common viruses that normally cause colds, but the Ad5 virus used in the HVTN 505 study’s vaccine regimen had been disabled so that it could not cause a cold or other respiratory illness.

Neither the DNA-based vaccine nor the Ad5 vaccine could infect study participants with HIV. Both vaccines had previously been given to hundreds of people in earlier clinical trials. No one had acquired HIV infection through immunizations with either vaccine because they both lack many of the pieces of the virus that are required to cause infection. Unlike other vaccines, such as those designed to combat influenza, these investigational HIV vaccines are not made from live, killed or attenuated (weakened) HIV. Therefore, it is impossible to acquire HIV infection or develop AIDS from the vaccines.

4. How many participants were involved, and what were the criteria for participating?
  The HVTN 505 study team enrolled 2,504 HIV-negative men who have sex with men and transgender people who have sex with men. The volunteers were 18 to 50 years old and lived in the United States. The study required that all male volunteers at time of enrollment be circumcised and all participants be free of antibodies to the Ad5 common cold virus. The circumcision and Ad5 requirements were implemented in light of an HIV vaccine clinical trial, known as the Step Study, which found in 2007 an increased number of HIV infections among vaccine recipients, particularly those who were not circumcised and/or had Ad5 antibodies.

 

5. Where was the study conducted? 
 

The study was conducted at 21 sites in the following 19 U.S. cities:

  • Annandale, Va.
  • Atlanta, Ga.
  • Aurora, Colo.
  • Bethesda, Md.
  • Birmingham, Ala.
  • Boston, Mass.
  • Chicago, Ill.
  • Cleveland, Ohio
  • Dallas, Texas
  • Decatur, Ga.
  • Houston, Texas
  • Los Angeles, Calif.
  • Orlando, Fla.
  • Nashville, Tenn.
  • New York, N.Y.
  • Philadelphia, Pa.
  • Rochester, N.Y.
  • San Francisco, Calif.
  • Seattle, Wash.
6. What was the design of the study?
  The HVTN 505 is a Phase IIb, randomized, placebo-controlled clinical trial. This means neither the study participants nor the clinical staff knew who received the investigational vaccine regimen and who received the placebo injections. Of the 2,504 participants, 1,250 volunteers were selected at random to receive the investigational vaccine regimen and 1,244 participants received the placebo injections.

 

7. What safety measures were in place to protect the study participants?
 

The well-being and safety of study participants is always our top priority. Before the HVTN 505 study began, its protocol was independently reviewed by NIAID, the U.S. Food and Drug Administration, a centralized institutional review board (IRB), and IRBs at individual sites where HVTN 505 was going to be conducted. These reviews were done to ensure that the study would be scientifically, ethically and clinically appropriate and that it would adhere to accepted standards for protecting human clinical research participants.

Additionally, an independent data and safety monitoring board (DSMB) composed of clinical research experts, statisticians, ethicists and community representatives conducted regularly scheduled interim analyses of HVTN 505’s clinical data. Furthermore, new HIV infections were monitored  as they were diagnosed to keep the closest possible watch on the safety of the study participants. The DSMB met 8 times to review the HVTN 505 study data since the trial’s 2009 launch.

Each HVTN 505 study participant received the best available HIV prevention services, including risk-reduction assessments, counseling on how to avoid HIV exposure, free condoms, and guidance on how to access HIV prevention services in the local community.

HVTN 505’s enrollment criteria also were designed to protect the study participants because the Ad5 vaccine is similar but distinct from the Ad5 vaccine evaluated in an HIV vaccine study known as Step (Statement: Immunizations Are Discontinued in Two HIV Vaccine Trials). Specifically, the study was limited to men in the United States who have sex with men who were circumcised and who did not have Ad5 antibodies at time of enrollment. This requirement was in place because there were more HIV infections among male vaccine recipients in the Step study who were not circumcised and who had Ad5 antibodies at enrollment than among those participants with the same characteristics who received the placebo injection. Conversely, Step vaccine recipients who were circumcised and without Ad5 antibodies at enrollment had similar rates of HIV infection to those who received the placebo vaccine.

8. What were the results of the April 22, 2013, DSMB review of the HVTN 505 interim study data?
 

During its scheduled interim review, the HVTN 505 DSMB found that the investigational vaccine regimen neither prevented HIV infection nor reduced viral load among vaccine recipients who later became infected with the virus. The DSMB examined information gathered from 1,250 volunteers who received the investigational vaccine regimen and 1,244 volunteers who received the placebo vaccine. The primary analysis looked at volunteers who were diagnosed with HIV infection after having been in the study a minimum of 28 weeks. This was done to enable enough time for the vaccine regimen to be given and stimulate an immune response. In this analysis, 27 HIV infections occurred among the vaccine recipients, and 21 HIV infections occurred among the placebo vaccine recipients. Among volunteers who became HIV-infected during the first 28 weeks of the study, 14 cases of HIV infection occurred among those who received the investigational vaccine regimen, and 9 HIV infections occurred among the placebo vaccine recipients.

In addition, the DSMB found that the vaccine failed to reduce viral load among 30 volunteers (15 vaccine recipients and15 placebo recipients) who acquired HIV infection at least 28 weeks after entering the study and who had 20 weeks of viral load data that could be evaluated.

Based on these findings, the DSMB recommended that no further injections of the investigational vaccine regimen be administered. As the trial’s sponsor, NIAID concurred with the DSMB’s recommendation and instructed all HVTN 505 study sites to immediately cease administering injections but continue follow-up with study participants and further evaluate the trial data.

9. Did the investigational vaccine regimen cause participants to have an increased risk for HIV infection?
  There was a non-statistically significant increase in the number of HIV infections among volunteers in the investigational vaccine group compared to the placebo group. It is not clear why this happened. Based on the finding, the DSMB recommended closer follow-up of participants beyond their month 24 study visit. NIAID agreed, and with the study investigators will be amending the study protocol to allow for closer, extended follow up of the vaccine recipients.

 

10. Why did you test another Ad5-based vaccine in people if the Ad5-based vaccine evaluated in the Step study may have increased volunteers’ susceptibility to HIV infection?
 

Based on what was known about the Step study findings, there were no signs of increased susceptibility to HIV infection among male vaccine recipients who were circumcised and lacked antibody responses to Ad5 at enrollment. That is why the HVTN 505 study was designed to include only those male volunteers with these characteristics. Although all clinical trials carry some risks, there was no information to suggest that the two-part vaccine strategy starting with a different priming vaccine also presented a safety risk in this population.

Further, there are distinct differences between the vaccine regimen developed by the VRC and the vaccine tested in the Step study. For example, HVTN 505 featured a DNA-based priming immunization while the Step study tested an Ad5-based vaccine as a single product. Additionally, the vaccines evaluated in both studies differ in their HIV genetic makeup, construction, dosing schedule, number of doses, and the types of immune responses they induce.

11. What will happen to the study participants now?
 

The study investigators are contacting all participants to inform them of the DSMB’s findings and NIAID’s decision to halt injections. Study volunteers are being asked to report to their specific clinic sites over the next few weeks to find out whether they received the investigational vaccines or placebo injections. The study investigators will continue following each participant for five years after their enrollment in the trial.

Individuals who became HIV-infected during the trial have been referred to local health services for appropriate care and treatment. (See question 12.)

12. What care and treatment were given to participants who became infected with HIV during the study?
  The study teams at each site in the 19 cities where HVTN 505 was conducted have ensured that participants who acquired HIV infection during the study obtained access to the highest quality of medical care and HIV treatment available in their communities.

 

13. Where can I find more information about this study?
  Please see the HVTN’s Web site at www.Hopetakesaction.org or at the study listing on ClinicalTrials.gov.

 

Media inquiries may be directed to the NIAID Office of Communications at 301-402-1663, niaidnews@niaid.nih.gov.

 




NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at www.niaid.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Last Updated April 25, 2013

Last Reviewed April 25, 2013