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Haynes: Centralized Envelope Phase I Study Abstracts continued

Submitted December 15, 2011 (Interim Report)

Over the past year, the 5 gp 160 DNA vaccines have been manufactured and released. They were fill/finished as 3 vaccines – Wildtype Clade B HIV-1 1059, Group M Consensus (Con-S), and a combination of the 3 mosaics. All three vaccines have been released and are currently on a stability testing program. 4 mg of the WT B, Con-S and 1.33 mg of each of the 3 mosaic DNAs will be administered.

Five NYVAC gp 120 env pre-virus seeds are under development. The NYVAC gp160 Envs and gp140 Envs were shown to be unstable. Accelerated development called for Dr. Jacobs to develop 2 NYVAC and Dr. Esteban to develop 3 NYVAC seed stocks. Dr. Esteban and Dr. Jacob’s laboratory were audited for their cGMP compliance in 1Q11. Seed stocks have been generated for all 5 gp 120 NYVACs.

DAIDS is directing the manufacture of the DNA and NYVAC vaccines and is also supplying the regulatory support for the pre-IND and IND. DAIDS, ABL, CHAVI, SRI, FNIH and others have participated on bi-weekly conference calls over the past year to review progress and problems for the products. Under direction by SRI, who were hired as a subcontractor this year, they have also been writing a pre-IND document to be submitted to the FDA in January/February 2012. The HVTN has been working on the clinical trial protocol for testing the DNA and NYVAC vaccines in humans.

Submitted February 1, 2011

The genetic diversity of HIV-1 is a major hurdle for the development of a successful preventive vaccine. The regimen that will be used to test the centralized genes in the phase 1 study consists of two priming mmunizations with DNA inserts (produced by NIH VRC), and then two boosts with the NYVAC vaccinia vector containing the same experimental inserts. The primary outcome will be safety, as measured by clinical and laboratory toxicity. The secondary outcome will be immunogenicity as measured by humoral, cell-mediated, and mucosal immune responses to the HIV-1 vaccine from blood samples obtained at various time points after immunization.

For the NYVAC construct, Dr. Bert Jacob’s lab had initiated preliminary work on the NYVAC gp160 seed vaccine stock; when NIAID/DAIDS conducted a cGMP compliance audit the NYVacgp160s were found to be unstable (not an unexpected finding) . NYVAC gp140 env seed stock is now under development. To accelerate and maintain time points and meet milestones, Dr. Mariano Esteban’s lab was added for NYVAC seed stock development. Dr. Esteban’s lab will be audited for cGMP in early 2011. The NYVAC construction team have successfully made the five NYVAC constructs for the trial and the project is now on track.

DAIDS has completed cGMP manufacturing all five of the gp160 DNA vaccines at Althea. The fill/finish is anticipated by first quarter 2011. IDT has been chosen to manufacture the NYVAC vaccines, and the estimated timeline for manufacture of all five vaccines is twelve to eighteen months.

Bi-weekly calls are conducted with the group to facilitate communication on the progress of the constructs, protocol and animal immunogenicity studies. It is estimated that a new target date for requesting the pre-IND meeting with the FDA would be April 1 at the earliest with the meeting to take place in June.

The protocol concept has been written and approved by the HVTN SAG (Scientific Advisory Group). An HVTN protocol development team has been created and a protocol has been drafted. Timing for finalizing the protocol depends on when manufacturing of all the products will be completed and if any issues are identified in this process such as from FDA interactions.

Submitted June 30, 2010 (Interim Report)

The genetic diversity of HIV-1 is a major hurdle for the development of a successful preventive vaccine. Over the past two decades, extensive viral sequencing has enabled an in silico approach to immunogen design to be developed, and substantial preclinical progress has been made. Centralized genes have now been identified which, as predicted in silico, have been proven to substantially improve the breadth of T cell reactivity, particularly CD8+ T-cells, in small animals as well as in non-human primates. A collaborative group, led by Dr. Barton Haynes at Duke and comprised of the Bill and Melinda Gates Foundation (BMGF) and their vaccine development arm, the Collaboration for AIDS Vaccine Discovery (CAVD), the Center for HIV/AIDS Vaccine Immunology (CHAVI), the NIH Division of AIDS (DAIDS), and the NIAID HIV Vaccine Trials Network (HVTN) with support from the Foundation of the NIH, joined in a full partnership to carry out a phase 1 scientific study to directly compare a number of types of T cell immunogens, in order to clarify the area of T cell immunogen design and to optimize vaccine insert immunogenicity in the face of expanding diversity of HIV-1.

The regimen that will be used to test the centralized genes in the phase 1 study consists of two priming immunizations with DNA inserts (produced by NIH DAIDS), and then two boosts with the NYVAC vaccinia vector containing the same experimental inserts. The primary outcome will be safety, as measured by clinical and laboratory toxicity. The secondary outcome will be immunogenicity as measured by humoral, cell-mediated, and mucosal immune responses to the HIV-1 vaccine from blood samples obtained at various time points after immunization.

Specifically, group M consensus envelope and trivalent mosaic envelopes (both of which were designed by in silico modeling and are predicted to be superior than wildtype envelope) will be compared to a monovalent wild-type transmitted clade B envelope in a 3 arm phase 1 immunogenicity clinical trial. The mosaic antigens have been designed based on the current Los Alamos database, a set that includes more full length envelopes sampled globally from more than 2000 individuals with a large set of sequences of transmitted viruses primarily from the CHAVI database.

Our selection of the natural strains to be used for the comparison is based on the following criteria. For the monovalent natural antigen, we will use the single transmitted virus that is the best choice in terms of providing coverage of potential T cell epitopes in the global database. The database is biased towards B clade envelopes, so the single best acute Env is a B clade representative. Vaccine antigens have been selected from among available SGA sequenced acute samples representing a transmitted virus. Therefore, this study, although primarily a T cell study, will also provide important additional data regarding the ability of a transmitted envelope vaccine to elicit neutralizing antibodies.

 

 
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