Status of NIAID Adenovirus-based Vaccine Studies
Last fall, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, paused, delayed, and/or modified vaccinations in eleven of its preventive and therapeutic HIV/AIDS, malaria and Ebola virus vaccine clinical trials involving adenovirus-based vaccine vectors. Adenovirus is a common virus that normally causes upper respiratory infections such as the common cold. This action was taken based on preliminary findings from the STEP/HVTN 502 HIV vaccine clinical trial, which used the Merck-developed adenovirus type 5 (rAd5) as a carrier — or vector — for synthetic HIV genes in the investigational vaccine that was being tested.
Although the vaccine used in the STEP study did not cause HIV infection, researchers found a greater number of HIV infections among those participants who received the vaccine, particularly those participants who had higher pre-existing immunity to adenovirus serotype 5 (Ad5) from a prior natural infection. Researchers are uncertain whether or how the vaccine may have contributed to an increased risk of contracting HIV and are continuing to explore the data for answers.
In the interest of the safety of our clinical trials volunteers, NIAID voluntarily paused several of its vaccine studies that involved adenovirus-based vaccine vectors to allow time to assess the STEP study data. An update on each of the studies is described below:
HIV Vaccines
STEP/HVTN 502
In September 2007, NIAID, Merck & Co., and the NIAID-funded HIV Vaccine Trials Network (HVTN) permanently ended immunizations in the Phase II HIV vaccine trial known as the STEP or HVTN 502 study involving the Merck-developed rAd5 vaccine candidate based on findings that the vaccine neither prevented HIV infection nor had an effect on virus levels in those who became infected. Further, researchers found a higher number of HIV infections among those who received the vaccine in comparison to placebo, particularly among those volunteers who had pre-existing antibodies to Ad5. The study, which began in December 2004, enrolled 3,000 volunteers in Australia, Brazil, Canada, the Dominican Republic, Haiti, Jamaica, Peru, Puerto Rico, and the United States.
Current status: Study investigators began unblinding trial volunteers in mid-November 2007. Follow-up of study participants is continuing, and a new protocol is being developed to enable researchers to continue follow-up and counseling of study participants. The study’s data continue to be analyzed for clues as to why there were a greater number of infections among those who received the vaccine, but since the study was not designed to answer this question, the investigators believe it is possible that the data may never fully reveal the reason for the increased risk to vaccine recipients.
Phambili/HVTN 503
The Phambili/HVTN 503 study, which began in January 2007, involved the same Merck candidate vaccine but was being conducted in South Africa. Based on the STEP findings, immunizations were initially paused in the Phambili study in September 2007 and permanently halted immunizations in the Phambili trial in October 2007.
Current status: The unblinding process for study volunteers began in late October 2007. Study volunteers continue to be followed and monitored by study investigators.
HVTN 071
This Phase 1b HIV vaccine clinical trial, which began in July 2007, involved the same Merck Adenovirus serotype 5 HIV-1 gag/pol/nef vaccine, given in a three-dose regimen. The trial provided additional information on the immune responses to the vaccine, as well as an evaluation of the safety and tolerability of the vaccine regimen. In order to look for relationships among the immune responses induced by the vaccine, all participants undergo leukapheresis, or large blood draw, after their last vaccination. Based on the STEP findings, immunizations were permanently halted in the HVTN 071 trial in September 2007. A total of 35 healthy, HIV-1–uninfected adults were enrolled at HVTN sites in the United States prior to halting enrollment and vaccination.
Current status: The study was open-label, and all study volunteers received vaccine. Vaccinations were stopped in September. Volunteers are continuing to be followed and monitored by study investigators, and study procedures are ongoing.
HVTN 069
This Phase Ib HIV vaccine study, which began enrolling participants in November 2006, is testing a prime-boost strategy involving two types of experimental vaccines created by NIAID’s Vaccine Research Center (VRC): a DNA vaccine and a replication-defective adenovirus serotype 5 vector vaccine (rAd5). The study, which was being conducted in the United States and Peru by NIAID’s HIV Vaccine Trials Network (HVTN), was designed to determine if the two vaccines are well-tolerated and if the rAd5 vaccine is safe and immunogenic when given by different routes: intramuscularly (into the muscle), intradermally (between layers of skin), and subcutaneously (under the skin). The study had achieved its target enrollment of 90 volunteers when it was paused, but not all participants had received the rAd5 booster.
The study participants were divided into three groups and given three DNA injections: an intramuscular injection at the time of enrollment, a second intramuscular injection one month later, and a third intramuscular injection two months after the time of enrollment. Twenty participants in group 1 received the adenovirus “boost” vaccine via intramuscular injection; 21 participants in group 2 received the adenovirus vaccine intradermally; and 20 participants in group 3 received a subcutaneous injection of the rAd5 vaccine six months after the initial DNA injection.
Current status: Researchers are continuing to follow all of the HVTN 069 study participants and monitor their safety. Additionally, the rAd5 vaccines are no longer being administered even though the rAd5 vaccine used in this study is different from the Merck rAd5 vaccine used in the STEP and Phambili vaccine studies.
HVTN 072
This Phase Ib HIV vaccine clinical trial, which had enrolled only 17 people since it began in August 2007, was designed to evaluate the safety and immunogenicity of both an adenovirus type 35 vaccine vector (rAd35) and an rAd5 vaccine vector when used either in a heterologous prime-boost combination with each other or used singularly as a booster in subjects primed with DNA vaccines. The study, which is being conducted in the United States through the HVTN, was designed to enroll healthy HIV-negative adults with high levels of pre-existing immunity from prior natural Ad5 infection.
Current status: Two HVTN 072 study volunteers received one dose of the rAd5 vaccine, and one study volunteer receive one vaccination dose of the rAd35 vaccine before the study was paused. Those volunteers will continue to be followed and monitored. No further vaccinations are to be administered in this study.
VRC 011
This Phase I HIV vaccine study, which is being conducted by the VRC on the NIH campus in Bethesda, Md., began in April 2006 and aimed to enroll 60 study volunteers. The study, which is testing a DNA-based vaccine and a rAd5 vector vaccine, involved screening participants for Ad5 antibodies. Half of the participants selected for the study had antibodies to Ad5, and the other half did not. The participants were randomly assigned to one of six possible vaccination schedules and differed by the type of vaccines given (DNA vaccine prime with rAd5 booster or rAd5 prime with rAd5 booster), how the priming vaccine was administered (intramuscularly, subcutaneously, or intradermally) and in the schedule of administration.
Current status: The protocol has been amended to restrict the use of the rAd5 vaccine to enrollees with no pre-existing immunity to Ad5 and at low risk of acquiring HIV. The protocol amendments were submitted to the Food and Drug Administration (FDA) and the study’s institutional review board before restarting the study, and all clinical trial participants underwent an additional informed consent process to continue participating in the study.
VRC 012
This Phase I HIV vaccine study, which began in May 2007, is being conducted by the VRC on the NIH campus in Bethesda, Md. The trial was designed to test the safety, immune response and side effects of two experimental HIV vaccines using rAd35 and rAd5. The study, which aimed to enroll 35 HIV-negative individuals, was being conducted in two phases. The first phase involved 15 participants who were to receive a one-time dose-escalation of the rAd35 vaccine. During the second phase of the study, 20 participants were to be randomly assigned to receive either the rAd35 or rAd5 vaccine as priming immunization and the other as a booster immunization
Current status: The study was revised to enroll only individuals at low risk of acquiring HIV and without prior immunity to Ad5 or Ad35. Enrollment and Ad35 vaccinations have been completed in the first phase of the study. Enrollment in the second phase of the study will commence only after review by the FDA.
VRC 101
This Phase I HIV vaccine study, which began in December 2005 on the NIH campus in Bethesda, Md., involves an investigational vaccine designed to treat HIV infection in individuals already infected with HIV. The study, which enrolled 17 adults, was testing the safety, tolerability, and immune response of a prime-boost vaccination regimen. The vaccination schedule consisted of three injections of a multiclade HIV plasmid DNA vaccine followed by one injection of a multiclade, recombinant adenoviral vector vaccine (rAd) developed by the VRC.
Current status: Only one clinical trial volunteer did not receive the final injection prior to the study’s pause. Adjustments to the study’s protocol are currently undergoing institutional review board examination, and the study is expected to be completed. All study volunteers will continue to be followed and monitored.
PAVE 100
This Phase IIb HIV vaccine study was not launched as originally planned in late September 2007. The study was designed to test a vaccine featuring a mixture of six DNA plasmids representing multiple HIV genes from multiple subtypes used as a priming immunization and a mixture of four rAd5 vectors with matching inserts as a heterologous booster immunization. The VRC-developed vaccine was planned to be tested in 8,500 participants in East Africa, Southern Africa, and the Americas.
Current status: NIAID and its fellow members of the Partnership for AIDS Vaccine Evaluation (PAVE) are examining how best to redesign the study in light of the STEP findings and are conferring with scientific and community partners on how this regimen should be evaluated further.
Malaria Vaccine
DMID 05-0050
This Phase I malaria vaccine study, which began in December 2006, is a randomized, controlled, dose-escalation trial designed to determine if an investigational malaria vaccine is safe, immunogenic and well-tolerated in healthy adults ages to 18 to 45. The trial, which is being conducted at two U.S. sites and expected to enroll 72 men and women, is testing a rAd35-based vaccine to combat falciparum malaria.
Current status: The study’s safety monitoring committee (SMC) recommended that the trial remain paused until each of the participants’ level of pre-immunization neutralizing antibody to Ad35 can be obtained; those volunteers with demonstrated pre-existing neutralizing antibody levels to Ad35 will be excluded from continued participation in the study. Additionally, the SMC recommended to revise the study’s informed consent and to reconsent the participating study volunteers. Further, the protocol will be revised to require pre-screening for Ad35 antibodies and to exclude those individuals with the antibodies. The SMC also proposed that the protocol require HIV status checks of study participants at the end of one year. These revisions will be put forth for regulatory review.
Ebola Vaccine
VRC 205
This Phase I vaccine study, which began in September 2006, is designed to test a VRC-developed investigational preventive Ebola virus vaccine using a recombinant Ebola adenovirus type 5 vector vaccine in healthy adults. The secondary objectives of the study are to evaluate immune responses and Ad5 antibodies up to 48 weeks after vaccination.
Current status: The study was not paused but is undergoing a scheduled review by the Data and Safety Monitoring Board and the FDA prior to starting the next dose level. VRC researchers plan to only enroll volunteers at low risk of HIV infection.
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