Do clades matter for HIV vaccines?

HIV is the most genetically diverse virus known (see Primer). HIV is presently divided into nine distinct subtypes, or clades. Clades can be thought of as branches on a family tree. HIV is also one of the most rapidly changing viruses known today. High rates of mutation and recombination are constantly giving rise to new viral versions or ‘strains.’

The broad diversity of HIV leads to one of the biggest scientific unknowns facing AIDS vaccine developers: Is a single “universal” vaccine against all versions of HIV possible? Or will it be necessary to make many different vaccines, each tailored to the most common versions of HIV in a given region? Even worse, could it mean that a new vaccine might be needed every year, as with flu vaccines?

The answers to these questions will influence how quickly a successful AIDS vaccine can be found and distributed around the world. It will be a huge undertaking to manufacture and distribute a single approved vaccine. Doing it with many different vaccines, or again every year, could be a nightmare.

The issue of HIV diversity has also come up in planning vaccine trials. Clades are roughly grouped by geographic region. Trial sponsors, scientists and politicians have all asked whether it makes sense to conduct trials of vaccine candidates that do not match the host country’s main clade.

Right now, there is no clear answer to the question: Do clades matter for HIV vaccines? One reason for this uncertainty is that the clade system (which is based on genetic sequences of the virus) is only one possible way of sorting viruses. Another option is to sort HIV versions by the immune responses that they cause. This approach is called organizing viruses by ‘immunotype.’ (Different versions of HIV cause different immune responses in people. These responses can temporarily control the virus which is why most people with HIV do not get sick right away.)

This approach could be important since immune responses are what really matter for vaccines. Vaccine educators in the fishing district of Rakai, Uganda use this explanation: A range of nets is used to catch different species of fish, according to their size. Grouping fish (viruses) by their color (clade) does not always give information about the best net (vaccine) to catch them.

There are other obstacles to answering the diversity question. New approaches for sequencing the genes of HIV have helped uncover aspects of viral diversity beyond the broad categories of clade. For example, there are parts of the world where the most common virus is a recombinant strain— a genetic patchwork of two different clades. Ongoing studies in Tanzania are looking closely at viruses isolated from highly-exposed women bar workers. Researchers Francine McCutchan (Henry M. Jackson Foundation, US) and Michael Hoelscher (University of Munich, Germany) are finding that many women carry new recombinant viruses. Some of these women seem to have been infected with more than one clade.

So how can the world find out whether or not clade—or other forms of viral diversity—matters for vaccines? In practice, it will mean studying the same vaccine in cladematched and -unmatched settings, to see if there are differences in protection. This is the only way to definitively resolve the issue.

But there are also clues to gather along the way. For instance, scientists are testing the ability of vaccine-generated immune responses to “recognize” fragments of viruses from other clades. To do this scientists collect blood samples containing immune responses from trial volunteers who have been given an experimental HIV vaccine based on a particular clade. Then in a lab these immune responses are exposed to pieces of viruses from other clades and the immune activity is measured. (Similar experiments have been done using samples from HIV-infected individuals.)

Using these techniques, scientists are finding some reasons for hope: vaccine-induced responses frequently recognize at least some versions of HIV from other clades— although the activity is different to that seen against the matched clade. So far this has been seen with one arm of the immune system (cellular immune responses) but not with the other (antibodies).

These data are encouraging to some. But many questions remain: Will cross-clade responses observed in labs translate into cross-clade protection in the real world? Are there other ways to group viruses that should be investigated? What is the best way to choose viral fragments, or ‘immunogens,’ for vaccines that will provide broad protection against diverse versions of HIV?

Perhaps most importantly, will countries and regions be open to testing vaccines which are not based on the local clade (un-matched) as well as ones that are based on the local clade (matched)? Here things look positive. Africa has several clinical trials underway, including some unmatched ones. These trials could help move the world closer to an answer to the clade question in the next few years. The African AIDS Vaccine Programme (see Global News) recently released a document recommending a combination of matched and un-matched trials in Africa. “I see a major shift,” says Jose Esparza, coordinator of the WHOUNAIDS HIV Vaccine Initiative. “There is widespread recognition across Africa that the question of diversity needs to be rigorously tested through well-designed clinical trials in matched and unmatched settings.”

The content in this issue of VAX is based on articles by Mark Boaz, Patricia Kahn, and Emily Bass, originally appearing in the May-August 2003 issue of IAVI Report.