One of the outstanding issues after the recent cessation of immunizations in the Merck/HVTN HIV vaccine trial (STEP/HVTN 502) was the fate of a sister trial, HVTN 503 (also known as the Phambili trial). Today, the outcome of the Data Safety Monitoring Board (DSMB) review of whether to continue the Phambili trial was officially announced. This is the pertinent quote from the press release issued by the South African AIDS Vaccine Initiative (SAAVI):
“Based on that additional review of the STEP data, an independent DSMB has now concluded that there is no basis for anticipating more favourable results in the South African clinical trial known as HVTN 503, or the ‘Phambili’ study. Therefore, the HVTN 503 oversight committee has permanently suspended immunisations and enrolment in the study in South Africa.”
NIAID also issued a statement and updated their Q&A about the two trials. What is particularly worrying about all three documents is the repeated suggestions that the vaccine may have enhanced susceptibility to HIV infection.
From the SAAVI statement:
"Based on data from the STEP Study, there is a possibility that people in the vaccine arm may have increased susceptibility to acquiring HIV infection."
From the NIAID statement:
"The Phambili DSMB also recommended that HVTN 503 volunteers be told whether they received the vaccine or placebo, be strongly encouraged to return to their study sites for protocol-related tests, and be counseled about the possibility that those who received the vaccine may have an increased susceptibility to acquiring HIV infections. Volunteers in the STEP study also will be counseled about this possibility, and discussions are under way to define the details of continued follow-up for the STEP volunteers, including when those participants will be told whether they received the vaccine or placebo.
Detailed analyses of the available data are being conducted, including analyses to better understand if there may be an increased susceptibility to acquiring HIV infection among those volunteers who received the vaccine."
From the NIAID Q&A:
"Volunteers in the HVTN 502 study are being encouraged to return to their study sites for HIV risk-reduction counseling and protocol-related tests, so that investigators can fully evaluate the effects of the vaccine on HIV acquisition, including whether there is any increased susceptibility to acquisition of HIV infection among those who received the vaccine. Volunteers are being counseled about the possibility that the investigational vaccine may have caused an increased susceptibility to acquiring HIV infection among those who received it."
"The DSMB for the HVTN 503 study also recommended that all volunteers be told whether they received vaccine or placebo and be strongly encouraged to return to their study sites for HIV risk-reduction counseling, protocol-related tests and counseling about the possibility that those who received the vaccine might have an increased susceptibility to acquiring HIV infection."
"Researchers, however, are analyzing available data to better understand if there may be an increased susceptibility to acquiring HIV infection among those volunteers who received the vaccine."
At the current time, it is completely unclear what these hints about enhancement are based upon. It may be that the South African DSMB decided that the difference between the vaccine and placebo arms for people that received at least two immunizations looked worrying enough to mention the possibility (there were 19 infections in the vaccine group and 11 in the placebo group), but it is important to stress that the results do not even amount to a statistical trend: the p value for this difference between the vaccine and placebo arms is p=0.1042.
Alternatively, perhaps the DSMB reviewed additional data that has not yet been made public. The official presentation of the data from the STEP/HVTN 502 trial is slated for the HVTN conference that is taking place in Seattle from November 7-9. In a very welcome move, the meeting has been opened to the public.
However, it is extremely frustrating that it appears that interested scientists, community members and trial participants will have to wrestle with the implications of these hints about enhancement without additional details until the HVTN conference. TAG will seek clarification about the content of today’s statements from NIAID and provide updates as new information becomes available. Future blog posts will also look at the literature on the potential associations between immune activation and susceptibility to HIV infection and discuss whether the data may have implications for vaccine research.
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