New Vaccines in the Pipeline

The growing number of candidates in pre-clinical development featured heavily in the vaccine presentations at Barcelona, along with updates on products already in clinical trials.

Many of these have been covered in recentIAVI Report articles (for example, see Merck’s DNA/adenovirus studies and Oxford/ Nairobi/IAVI’s DNA/MVA candidates, Mar-Apr 2002, p.1; Harriet Robinson’s DNA/MVA strategy, Oct-Dec 2001, p.13). Here, we focus on a few candidates that have received less coverage.


Envelope—CD4 complexes

The lack of success in developing vaccines that can neutralize a broad range of HIV subtypes—a property thought to offer the best hope of preventing initial infection—has been one of the field’s most frustrating impasses. But an antibody-inducing candidate developed by Tim Fouts and Anthony DeVico at the Institute of Human Virology (IHV, Baltimore) has now shown some early promise in the monkey model, as reported in a presentation by IHV director Robert Gallo. (This work was published shortly after the Barcelona meeting in PNAS 99:11842;2002.)

The IHV immunogen contains gp120 (or gp140) cross-linked to CD4, the T-cell surface molecule that binds HIV—causing a shape change in gp120 that reveals epitopes normally hidden from the immune system—and, in turn, initiating viral entry into the cell. When the gp120-CD4 complex was used to immunize monkeys, Gallo reported that it generated antibodies which neutralized primary strains from HIV subtypes A through E, regardless of their co-receptor use, but worked poorly against laboratory isolates. The researchers are now testing ways to enhance this response (for example, through use of a cholera toxin fragment that shows strong adjuvant activity) and, in collaboration with Merck, are evaluating the vaccine’s ability to protect monkeys against a SHIV challenge.

However, the vaccine they move into clinical development may look somewhat different, Gallo told the IAVI Report. To avoid possible safety and regulatory concerns over the use of CD4 in a vaccine, the IHV team has sought a replacement for the CD4 component. Through modeling studies, they have now found a promising substitute: an attenuated version of scorpion toxin, a molecule with a similar 3D structure to CD4 that seems to induce the same shape change in gp120. Although the gp120-toxin complex is still at an early stage, it is the most likely immunogen for further development as a vaccine.

GlaxoSmithKline’s protein vaccine

This candidate contains gp120 along with a Nef-Tat “fusion protein.” According to GSK’s Gerald Voss, speaking at the vaccine satellite meeting, the vaccine is formulated with a new adjuvant called AS02A, an oil-water emulsion containing the immunostimulants QS21 and 3D-MPL. ASO2A appears to stimulate both antibody and cell-mediated immune responses and showed a good safety record in GSK’s 1,300-person malaria vaccine trial. It is now being used in studies of several other (non-HIV) vaccine candidates.

Following a Phase I study of gp120 by itself, the complete vaccine entered clinical testing in February 2002 at 10 centers of the US-based HIV Vaccine Trials Network (HVTN). The 84-person trial will test the Nef-Tat protein alone and in combination with increasing doses of gp120, all in AS02A. Final results are expected in mid-2003. GSK also plans to study the vaccine as a therapeutic in HIV-positive volunteers.

Prior to launching the trial, the vaccine was found to protect rhesus macaques against challenge with a partially heterologous virus (SHIV89.6P, which differed from the vaccine strain by 20% in gp120 and 10% in Tat). Voss reported that these animals remain healthy three years after challenge.

Semliki Forest Virus (SFV)-based vaccines

New to the roster of viruses used to develop vaccine vectors, SFV is an alphavirus that is pathogenic in rodents but only rarely infects humans (so pre-existing immunity to the vector is seldom seen), and at most produces mild, flu-like symptoms. Peter Liljestrom (Karolinska Institute, Stockholm) described his team’s work on designing vectors from an attenuated SFV in which the viral structural genes are replaced by foreign antigens, rendering the vector non-infectious. To maximize safety, they are engineered to persist only transiently—yet they induce potent immune responses in mice and monkeys.

Liljestrom also presented data from challenge studies in a small number of monkeys. Four animals immunized with SFV-env (containing the SIV-PBj14 env gene) and then challenged with homologous SFV were protected from illness and death, and suppressed viral replication. (In the control group, one of four animals survived.) Protection was also seen in 2 of the 4 monkeys vaccinated with 6 SIV-J5 genes (env, gag, pol, nef, rev and tat)—first as naked DNA, followed by MVA-SIV 12 weeks later and finally by SFV-SIV—and then challenged with SIV-J5. The SFV boost appeared to be required for protection, since neither MVA-SIV alone (three immunizations) nor DNA plus 2 MVA boosts, protected against a J5 challenge.

Efforts are underway (through a partnership with IAVI and Bioption, a Stockholm-based biotechnology company) to produce SFV vectors carrying HIV subtype C antigens, for testing and use in India.