HIV gp120 Vaccine — VaxGen

Abstract

VaxGen is developing prophylactic vaccines against HIV-1 consisting of two recombinant gp120 surface proteins from different HIV-1 strains.1 The bivalent vaccines [AIDSVAX™ B/B and AIDSVAX™ B/E] are being evaluated in two phase III trials. The first multicentre phase III trial of AIDSVAX™ B/B, was conducted principally in Canada and the US but also at some sites in the Netherlands and Puerto Rico. The trial was completed at the end of 2002. The second phase III trial is being conducted in Thailand with the AIDSVAX™ B/E vaccine. VaxGen announced in July 2002 that it would be delaying its Biologics License Application (BLA) for AIDSVAX™ until 2004 to enable the company to fulfil preapproval manufacturing requirements.

AIDSVAX™ is based on an earlier monovalent gp120 vaccine developed by Genentech that was shown to be safe in humans. VaxGen (formerly Genenvax) was formed as a spin-off company from Genentech with the sole purpose of developing the gp120 vaccine.

VaxGen announced in July 2002 that the original License and Supply agreement with Genentech, signed in May 1997, had been amended. Under the revised agreement, Genentech maintains its right to market and sell AIDSVAX™ in North America, but has relinquished its options to commercialise the vaccine candidate in the rest of the world. Genentech’s earlier decision to waive its option to manufacture AIDSVAX™ has also been formalised in this agreement. Additionally, VaxGen’s royalty payments to Genentech for sales to the WHO or UN for underdeveloped nations have also been reduced by up to 50% and Genentech has extended the milestone date associated with VaxGen submitting an NDA.[1]

A $US120 million joint venture (Celltrion) has been formed between VaxGen and South Korean investors to manufacture more than 200 million doses of AIDSVAX™ a year. Celltrion will build and operate two biotechnology manufacturing facilities: a pilot plant in South San Francisco and a larger plant in Incheon, South Korea. VaxGen will retain a 44% interest in the new company, as well as any profit generated by the AIDS vaccine. If AIDSVAX™ wins regulatory approval, VaxGen is committed to purchasing a minimum of 87 million doses a year. Celltrion announced in July 2002 that it had acquired 24 acres of land in Incheon, South Korea, for the site of its major biologics manufacturing facility. The facility is scheduled to be ready for commercial operation by 2005.

The US FDA granted fast-track designations to the two vaccines AIDSVAX™ B/B and AIDSVAX™ B/E in December 2002.

The study volunteers included 5108 men who have sex with men and 309 atrisk women, all of whom were meant to be HIV negative when they joined the trial. During the 36-month trial, a total of seven injections were administered at months 0, 1, 6, 12, 18, 24 and 30. The ratio of vaccine to placebo recipients was 2:1.

On February 24 2003, VaxGen announced that AIDSVAX™ B/B did not prove effective in the trials conducted in North America and Europe. The study did not show a statistically significant reduction of HIV infection within the study population as a whole, which was the primary endpoint of the trial. However, the study did show a statistically significant reduction of HIV infection in certain vaccinated groups. Trial data indicate that black and Asian volunteers appeared to produce higher levels of antibodies against HIV. White and Hispanic volunteers appeared to develop consistently lower levels of protective antibodies following vaccination. VaxGen intends to conduct additional analyses to confirm if there was a direct correlation between the level of antibodies and the prevention of infection. The company intends to continue development of the vaccine through licensure, including any studies necessary to evaluate the protective effect seen among non-Caucasian populations.[2,3]

Following criticism in the media about the statistical analysis of the non- Caucasian data, VaxGen issued a statement on 27 February 2003 claiming that the analysis of data from the trial followed a statistical analysis plan that was agreed on in advance with the US FDA. The plan included analyses of various subgroups, including racial backgrounds.[4] Subsequently, VaxGen presented further analyses of the phase III data at the Keystone Symposia on 31 March 2003, and stated that the differences in vaccine efficacy observed between the Caucasian and non- Caucasian (Black, Asian and other) vaccinees could not have been due solely to chance.

In May 2003, VaxGen stated that it would only continue developing AIDSVAX™ if government agencies and philanthropic organisations provide the necessary funding.[5]

AIDSVAX™ B/E is designed to protect against strains of HIV-1 prevalent in Indonesia, Japan, Korea, Taiwan and Thailand. Like the North American study, this trial also includes an interim efficacy analysis, set for 24 months after completion of enrolment. Results from this trial are expected to be announced in the second half of 2003. This trial received its final favourable review from the DSMB in October 2002.

Based on this result, the National Institute of Allergy and Infectious Disease (NIAID) has decided to pursue only one of the two previously planned phase III trials involving immunisation with vCP1452 and AIDSVAX™ B/B. The NIAID will not conduct the North and South American phase III trial. It will, however, proceed with the planned ‘prime-boost’ phase III trial in Thailand, to evaluate the efficacy of a similar vaccine combination, ALVAC-HIV-vCP1521 and AIDSVAX™ B/E, both of which incorporate envelope antigens from the predominant circulating HIV (CRF_AE_01) in Thailand. The trial is expected to begin enrolling volunteers in March 2003. VaxGen was a awarded $US3.3 million contract to supply AIDSVAX™ B/E for the trial, which will be funded by the NIH and conducted by the US Army.

NIAID and the HIV Trials Network (HVTN) are conducting a phase II trial (HVTN 026), testing the immunogenicity of vCP1452 alone and in combination with AIDSVAX™ among populations in Brazil, Haiti, Peru and Trinidad and Tobago.