Merck researchers have announced promising results in animal studies of a new HIV vaccine approach based on using the common cold virus as a vehicle to introduce specific HIV genes into the body. This approach is intended to stimulate an immune response without the risk that HIV sequences could recombine with others to become more dangerous (a drawback of the widely discussed live attenuated vaccine approach).
Five different vaccine preparations and dummy vaccine were tested in monkeys. Four plasmid DNA vaccines were tested; these use small rings of bacterial DNA spliced with HIV DNA to introduce the viral material into the body. A study by Dr Michael Egan of Harvard Medical School last year found that a vaccine of this type could induce a strong virus specific cytotoxic lymphocyte reaction.
A common cold virus (adenovirus type 5) was used as the basis of the fifth Merck vaccine, and specific HIV genes from the gag region of the virus (the inner proteins) were stitched into the adenovirus. The researchers chose an adenovirus because it targets dendritic cells, which are also the first line of infection for HIV.
Fifteen monkeys were vaccinated, of which three received the adenovirus-based vaccine.
Only monkeys vaccinated with the adenovirus-based vaccine had strong CD4 responses and viral load reductions after being challenged with an extremely virulent form of SHIV (a genetically engineered combination of the monkey equivalent of HIV and HIV itself). Viral load in this group was reduced by 2-3 log (100 to 1,000 fold) compared to recipients of other vaccines in the study, and each monkey had undetectable viral load within two months. However, even the adenovirus group did not clear the virus altogether, suggesting that in some cases the vaccine will not prevent infection, but may cause people to become long-term non-progressors, and reduce the risk that they could transmit the virus to others.
Four of the six monkeys in the unvaccinated control group died within eight months of infection. Other vaccinated monkeys did not develop AIDS, but did experience declines in their CD4 cell counts in most cases, suggesting that their immune systems were less well protected against SHIV than the adenovirus group.
The Merck vaccine only induces cell-mediated immune responses, whereas previous vaccine approaches in most disease areas have tended to focus on producing antibodies. However, scientific opinion is divided over the usefulness of antibody responses in the control of HIV infection.
Merck researchers have also tested an approach called 'prime/boost', which uses a plasmid DNA vaccine followed by an adenovirus DNA vaccine, or vice versa. This may result in a powerful and sustained immune response, they believe, a view shared by other research groups including Dr Andrew McMichael's group at Oxford University. They are testing the prime/boost DNA vaccine approach in a study which has just started in Kenya.
The Merck vaccines are now being tested in human studies in healthy volunteers and also in people already infected with HIV. The study in HIV-positive individuals will test the vaccine in people on antiretroviral therapy who have had undetectable viral load (
After these initial safety studies are completed by the end of 2002, Merck will embark on larger efficacy studies if the approach proves safe and effective in the preliminary human studies. However, it may still take five to seven years to prove the effectiveness of a vaccine developed along these lines, according to company sources.