HIV vaccine candidates seek to make good on their early promise
by Jeannie Wraight and David Miller
Over the past several years, momentum for the development of an effective HIV vaccine has increased to unprecedented proportions. At present, there’s no small number of approaches to the development of an HIV vaccine both by academic institutions and biotech companies, with IAVI reporting thirty-nine ongoing clinical trials. Add this to the number of preclinical candidates and you have reason for a lot of hope for seeing an end to new HIV infections.
One such vaccine platform is being studied by PaxVax, a company with ongoing vaccine research in several infectious diseases in addition to HIV, including chikungunya, hepatitis A, Zika, and adenovirus. Dr. Jonathan Smith, Executive Vice President and Chief Scientific Officer, and Dr. Jeff Alexander, Vice President of Translational R&D, provided an overview on PaxVax’s current HIV vaccine program and how development is continually evolving with our growing knowledge base of immune responses.
PaxVax has received over $10 million in grants from the NIH and NIAID’s Division of Acquired Immunodeficiency Syndrome (DAIDS) for the development of their vaccine platform. This platform consists of two replication-competent adenovirus serotype 4 (Ad4) vector HIV vaccines that are used in conjunction with each other. The first vaccine component (Ad4-env Clade C) expresses an optimized HIV envelope protein derived from a clade C HIV strain. This vaccine is designed primarily to induce an effective antibody response. The second vaccine component (Ad4-mGag) is intended to induce broadly reactive T-cell responses. Both responses are essential for an efficacious vaccine.
PaxVax utilized live Adenovirus Types 4 (Ad4) vectors in both of their HIV vaccine candidates. One of the main differences between the PaxVax platform and other HIV vaccine candidates is that the AD4 vector used is given in pill form versus intramuscularly. This allows for the vaccine to affect the gut, creating a systemic and possibly a mucosal response. Used in pill form, AD4 vectors have been shown to be safe and have been utilized for decades by the U.S. military to inoculate our soldiers against acute respiratory disease caused by adenoviruses. Researchers at PaxVax are also considering employing an internasal delivery system, which would allow for a greater mucosal uptake.
The researchers at PaxVax are utilizing the growing knowledge of vaccine development in order to increase the probability of obtaining the best response and protection against HIV. These vaccines contain a number of gene inserts which incorporate particular fragments of HIV. PaxVax is focused on generating second generation gene inserts as well as second generation vectors. They’re currently refining their previous vaccines with different inserts to potentially induce a broader antibody response. They believe this approach, together with an improved and more robust AD4 vector, may induce a better antibody response, which may result in neutralizing HIV.
PaxVax researchers had previously deleted several of the non-essential genes in the E3 region of the adenovirus vector. According to Dr. Alexander, “We think we may have over-attenuated the virus because it became highly susceptible to the body’s innate response. Now the trick is to put them back in a way that doesn’t inhibit the transgene.” (A transgene is a segment of DNA containing a gene sequence that has been isolated from one organism and is introduced into a different organism.) “We’re now looking at maintaining as many of our E3 genes as possible and still get stable and robust expression of our HIV envelope genes.”
Although much has been learned from previous studies, such as the RV144 and STEP trials, vaccine researchers are still striving to determine the best means of stimulating an effective antibody response, which antibodies work best in neutralizing HIV, and what antigens could best facilitate immune control of HIV.
In addition to the work at PaxVax, other HIV vaccines are making their way through the preclinical and clinical stages to ascertain their protective ability against HIV. These include vaccine candidates receiving funding from the NIH as well as foundations and private financial institutions.
Bill and Melinda Gates have recently joined a team of other financiers supporting a company called Vir Biotechnology, which recently purchased an HIV vaccine that utilizes a cytomegalovirus vector to stimulate killer T cells. The vaccine candidate was designed at the OHSU’s Vaccine and Gene Therapy Institute in Beaverton, Oregon. The vaccine was shown in non-human primate studies to control SHIV in thirteen out of twenty-three rhesus macaques receiving either rhesus cytomegalovirus (RhCMV) vectors alone or RhCMV vectors followed by adenovirus 5 (Ad5) vectors. According to Nature, during autopsy “cell-associated SIV was only occasionally measurable at the limit of detection even with ultrasensitive assays, observations that indicate the possibility of eventual viral clearance.”
Through NIH grants, a vaccine company called Novavax is working in collaboration with the University of Alabama-Birmingham, Emory University, and Harvard Medical School to develop a pre-clinical, viral-like particle (VLP) HIV vaccine candidate. A VLP vaccine mimics the structure of HIV but doesn’t contain HIV viral genes. This vaccine is hoped to be active against a range of HIV strains and may produce a strong immune response by optimizing the expression of the HIV- 1 envelope.
Increased and continued support for the development of both preventive and therapeutic vaccines is essential to ending the thirty-five-plus-year battle against HIV. If just one of the vaccines currently being studied or envisioned by some of the best minds we can throw against this pandemic were to prove successful, the savings in lives, as well as dollars, would be astronomical. Costs of ART in low to middle-income countries hit $19 billion in 2015—despite having only reached half of the 36.7 million people living with HIV. This is a cost that is inevitably unsustainable and just like the lives HIV takes, will only continue to increase.
Jeannie Wraight is the former editor-in-chief and co-founder of HIV and HCV Haven (www.hivhaven.com) and a blogger and writer for TheBody.com. She is a member of the Board of Directors of Health People, a community-based organization in the South Bronx and an advisor to TRW (Teach me to Read and Write), a community-based organization in Kampala, Uganda. She lives with her husband in New York City.
David Miller is a long-term survivor and a veteran of ACT UP NY. He has been a member of the Bronx HIV CARE Network, the NYC HIV Planning Council Advisory Group and served on the Board of The AIDS Institute. He now lives in upstate New York, where he serves on the University of Rochester ACTG CAB.