What is Success in HVTN 702 and/or HVTN 705/HPX2008?


By: Dr. Larry Corey, HVTN, Seattle, WA, USA

Dr. Larry Corey, MD
Dr. Larry Corey, MD

We have two major studies in the field to test the concept of whether non-neutralizing antibodies can protect against HIV in the areas of the world most affected by the epidemic. In both instances, the vaccines were made specifically for the epidemic that we are tackling. The 702 vaccine regimen made by the Pox-Protein Public-Private Partnership (P5) is based upon data from RV144, and the strains and the study design are all building on the results from that study. During the interim years, much has happened in the HIV vaccine field including the sale of the original company that invented the gp120 proteins used in HVTN 702; Novartis was sold to GSK. There has been constancy in the leadership of the ALVAC vector program at Sanofi, which we are happy with. Success in 702 means an efficacy above what was achieved in RV144, hopefully at least a 50% reduction in new HIV infections over the first two years of the vaccination regimen, and a longer duration of efficacy with the continued booster dose we are giving in 702.

We have two major studies in the field to test the concept of whether non-neutralizing antibodies can protect against HIV in the areas of the world most affected by the epidemic. In both instances, the vaccines were made specifically for the epidemic that we are tackling. The 702 vaccine regimen made by the Pox-Protein Public-Private Partnership (P5) is based upon data from RV144, and the strains and the study design are all building on the results from that study. During the interim years, much has happened in the HIV vaccine field including the sale of the original company that invented the gp120 proteins used in HVTN 702; Novartis was sold to GSK. There has been constancy in the leadership of the ALVAC vector program at Sanofi, which we are happy with. Success in 702 means an efficacy above what was achieved in RV144, hopefully at least a 50% reduction in new HIV infections over the first two years of the vaccination regimen, and a longer duration of efficacy with the continued booster dose we are giving in 702.

Success does not mean immediate licensure of the vaccine for widespread use. Success means that we define whether antibodies to the V1V2 region of HIV’s surface proteins are still correlated with reduced HIV infection and/or whether the CD4 T-cell responses are still independently associated with HIV infection. Success leads to continued development of the program. This continued development takes several forms. One is to develop the manufacturing capabilities required to license a vaccine, to move the process of development from a research stage to an industrial stage. This is something necessary for both making the protein as well as the canarypox vector. Success also means increasing the durability of the response (how long it lasts). Should this be done with another adjuvant? GSK has used the AS01B adjuvant in its recently licensed, highly effective varicella zoster (shingles) vaccine, and phase 1 studies using it with the 702 vaccine regimen have begun. If these show greater durability, then bridging studies to replace the MF59 adjuvant with AS01B might be considered. Lastly, continued development might be to redesign the vaccines to utilize recently discovered strains of clade C that would enhance V2 responses, or even to add the strain from the RV144 trial called A244 to the vaccine regimen. While one could groan at the length of this process, success also means progress. This could include studies to introduce the vaccine to adolescent populations, new regions of the world, or new populations such as Men who have Sex with Men (MSM).

All of these options are available and are under consideration depending upon the degree of protection, the strength of any potential correlate of protection, and the cost and time of bringing a commercially viable vaccine to sub-Saharan Africa. One could say that 702 is just the beginning of the march for the regimen.

The HVTN 705/HPX2008 study is also in the early stages of the march to potential global efficacy. From the beginning, the construction of the vaccine has been developed to have global coverage. The recent data from HVTN 117 shows that adding the clade C mosaic vaccine and the addition of a clade C gp140 boost enhanced the immune responses in people that were associated with protection shown in the nonhuman primate experiments, as well as enhanced clade C immune responses. Again, the degree of efficacy and any potential human correlate of protection that is associated with efficacy will drive future plans. Will the addition of another protein enhance antibody responses and durability? Can the regimen be compressed more to allow protective immunity to be seen earlier? Can the addition of a novel vector, such as MVA (related to smallpox), enhance immune responses that are associated with reduction of new HIV infections?

Experiments to extend the results from women to heterosexual men, MSM, and transgender women and men will also need to be performed. In addition, tackling other populations at risk of infection are also needed.

One can ask the question: why do these efficacy studies if so much more work is required to bring the vaccine to people? The answer is an easy one. The risk of an HIV vaccine is high, and we need to develop an intermediate step before private and/or public funders can be brought to the table. Funders will need to make a substantial financial investment to meet manufacturing and distribution guidelines for licensure. The HVTN is lucky to have the kind of dedicated partners that will take such risks. We are appreciative of our funders at DAIDS and the Bill and Melinda Gates Foundation, and our pharmaceutical collaborators at Janssen, Sanofi, and GSK.

* Dr. Larry Corey is the Principal Investigator for the HVTN.