A vaccine developed by Merck is likely to be the first adenovirus-based vaccine to be put into a large scale clinical trial, it emerged this week at the AIDS Vaccine 2004 meeting in Lausanne, Switzerland.
Merck's vaccine has given the best cellular immune responses to HIV proteins seen to date. It is based on a common-cold-type virus called an adenovirus, made unable to reproduce fully in ordinary human cells, into which HIV protein gene sequences have been inserted (gag, pol and nef). As many as 75% of volunteers in clinical trials have measurable responses, although this falls to 50% or less if they have prior immune responses to the adenovirus used (Ad5).
Unfortunately, around 40% of adults in the USA and Western Europe have significant levels of Ad5 immunity and this figure rises to 70% or 80%, including many with very high antibody levels, in countries such as South Africa, Thailand, and in other regions where the prevalence of HIV is highest. Methods to overcome pre-existing immunity which seem to work in monkeys – priming with a DNA vaccine or boosting with a canarypox-based vaccine – have not worked when tried in humans. Increasing adenovirus dose has its limits – at the highest dose used, those volunteers who do NOT have prior Ad5 immunity occasionally become feverish, 24-48 hours after the injection.
Merck’s current lead vaccine candidates also may or may not be limited in global relevance in using gene sequences from subtype B strains of HIV, which are prevalent in Europe, the Americas and Australasia, but are rare in the countries most seriously affected by HIV.
Merck is developing alternative, less common, strains of adenovirus as the basis for a future vaccine. Ad11 and Ad35 seem not to be nearly as widespread as Ad5 in the global community, and versions of these have now been developed to grow in the same cell lines used for Ad5 production. Initial animal studies suggest these may be usable, although immune responses may not be as strong as with Ad5. One option may be to modify Ad5 so the vaccine is not affected by pre-existing immunity, by altering, deleting or replacing one of the outer surface (envelope) proteins. There might be advantages to using two different strains to prime and boost an immune response.
In view of the limitations of the current Merck vaccine, Dr Larry Corey, who leads the publicly-funded US HIV Vaccine Trials Network, plans that it should be used for a “proof of concept” trial in a selected high-risk population. It would probably mean recruiting 2000 gay men and 1000 others at high risk of HIV in North America, the Caribbean and South America where subtype B viruses are predominant. The trial protocol will exclude volunteers above a set level of pre-existing immunity to Ad5, to side-step that problem.
Dr Corey argued that with the present state of knowledge, several relatively small trials showing some signs of protection using different vaccine systems could be of more value scientifically than one or two big licensing-type trials, and a better use of resources.
There are potentially difficult questions about how to deal with a situation where a trial gave results that strongly suggested efficacy but fell short of enabling a product to be licensed. Would it still be acceptable to run a vaccine trial with a placebo arm? Yet without such a trial, there would be no further access to the vaccine.
In practice, if it is clear that the vaccine under consideration - like Merck’s Ad5-based candidate - will not be the final product, then this problem may be less difficult than it would otherwise be. Just for once, running a potentially under-powered efficacy trial might not be such a bad idea.
Barouch D et al. Immunogenicity of heterologous prime-boost vaccine regimens involving adenovirus serotypes 11 and 35. AIDS Vaccine 04, Lausanne, abstract 14, 2004.
Isaacs R. Impact of pre-existing immunity on the immunogenicity of Ad5-based vaccines. AIDS Vaccine 04, Lausanne, abstract 69, 2004.