IAVI Report - January / February 2002

Malegapuru William Makgoba is president of South Africa’s Medical Research Council (MRC) and is involved in AIDS vaccine development on a national, continental and global level. He began his scientific career as a child, tending his family’s sheep and goats in Sekhukhueland, South Africa and paying close attention to the details of their life cycles, experiences he describes in his 1997 memoir “Mokoko.” From there he went on to receive M.B. and Ch.B. degrees from the University of Natal in 1976 and a Ph.D. in human immunogenetics from Oxford University in 1983, followed by further research at the National Cancer Institute in Bethesda. In addition to his MRC role, Makgoba chairs the steering committee of the African AIDS Vaccine Programme and is a member of IAVI’s Board of Directors.

What do you see as SAAVI’s primary role?
SAAVI has roles at three different levels. One has to do with national buy-in on development and testing of vaccines in South Africa. Then, because South Africa is one of the few countries in the region with a research infrastructure and a history of doing basic science research, particularly in vaccine development, SAAVI plays a role in galvanizing the little expertise that exists and becoming its focal point. SAAVI’s third role is to assist in connecting the nation and the region to global efforts on finding a vaccine, accelerating access, and providing any other assistance needed. A fourth issue is that, particularly in the MRC, we have a long history in the culture of ethics and regulatory processes. SAAVI can link whoever wants to be involved in trials in South Africa and SADC [the Southern African Development Community] with reasonable ethical committees, reasonable regulatory processes and institutions like the Medicines Control Council [MCC].

In your plenary talk at last year’s AIDS Vaccine Conference in Philadelphia, you said that all South African vaccine trials will take place under the auspices of SAAVI.
That is “law” in South Africa. SAAVI was established precisely for this purpose: to develop and test vaccines in a coherent coordinated manner that is standardized throughout the country.

So all vaccine trials coming in from the outside will go through SAAVI to the sites.
Yes. We don’t want to find people doing research in our backyard and not being held accountable. That has happened throughout the history of research in various clinical trials. We are trying to protect our own citizens and have a process that is really coordinated, coherent and accountable--from the scientists to the highest political accountability.

Does the decision to approve vaccine trials still lie with Medicines Control Council?
Yes. But SAAVI works very closely with the MCC.

How will SAAVI coordinate these activities?
SAAVI has created an infrastructure so that all the trial sites in South Africa talk to each other and do things together. They are managed almost centrally. Let me add this proviso: SAAVI reports every quarter to the board of the MRC and the Department of Health, which connects us to the political structure of our country. That will continue when we start clinical trials.

Where does the African AIDS Vaccine Program fit into all of this?
The AAVP is actually based on the concept of SAAVI, but is a continental process to bring out all the countries in Africa where there is a bit of infrastructure in basic science, ethics, regulatory processes, population studies and so forth. It will bring African leadership into the process of vaccine trials.

And it is based on the same principle as SAAVI, which is to protect our societies against the fly-by-night researchers who want to come into Africa and simply set up shop. We come from a history of abuse and exploitation that happened because there was no infrastructure in one country, no capacity in another. So people come and do what they like. But it will also provide African scientists and leaders with a forum around which they can share common problems. For example, the AAVP is going to be linked to the African Union, which is an important political power.

What mechanisms can help collaborating countries reach consensus on some of the thorny issues raised by vaccine trials?
There is nothing that helps people understand each other except dialogue. Part of the reason why SAAVI was started was to begin a dialogue within South Africa and within the region. That dialogue is now being extended to the African continent with the AAVP. We could never do that in the old era of colonial powers when people were just interested in dividing Africa and carving it up for their own uses.

A few years ago, people worried that too little attention went to vaccines based on subtypes prevalent in developing countries. Have we now gone too far in the other direction, in terms of countries wanting to test only vaccines made from local strains?
Let me play Devil’s advocate. There is a real reason to tribalize clades. First, we don’t understand this phenomenon of cross-clade immune responses in detail. Second, we don’t understand in detail how cross-reactivity translates into cross-protection. We know how HLA diversity [diversity of a certain set of genes] influences the type of immune responses you get, depending on the particular antigen used. If you have a clade C vaccine that induces immune responses which cross-react with HIV clade A, and a clade A vaccine that cross-reacts with C, we don’t know which one of those will provide the best cross-protection. You cannot answer that question by streamlining scientific thinking. You can only answer that question if you know what a clade A does, and you know what a clade C does.

South African scientists have made a clade C consensus sequence. Botswana also has one. Is this level of national specificity necessary? We don’t understand what each one of them will do. The idea is not to be competing. But in South Africa, we need to test a clade C because that is the prevalent strain here. We need to test a clade C that is closer to our own strains. That doesn’t mean we shouldn’t take a clade C from China or from another place, but for heaven’s sake, we do need to test our own clade C before we can understand what the closer relatives can do.

If a non-clade C vaccine shows efficacy—for example, in the ongoing VaxGen trials, how will that affect trial design in South Africa?
We would have to rethink how we would do our efficacy trials.

Would it be fair to say that you might build it in as a placebo?
It will have to be done. It would seem to be unethical not to do that.

You said that one of SAAVI’s aims is to shift from the traditional MRC approach to more of a business model. What does that mean?
Business models are based on deliverables. Traditional scientific models are not based on deliverables. That is the difference. We are trying to maintain the excitement and creativity of science and also raise social consciousness among scientists that there are deliverables.

Speaking of deliverables, next year South Africa will be producing DNA and MVA vaccines to be tested here. Do you anticipate scaling up production if these vaccines move into Phase III?
I don’t think they will be produced in South Africa [for Phase III]. But we are discussing this with various arms of government to try and develop venture capitals to support entities that can actually manufacture vaccines. I think that is a long way away, but it is part of the long term strategy for SAAVI.

Right now there is an ongoing lawsuit about the use of nevirapine, and the government is publicly expressing skepticism about the safety of anti-HIV medicines. Does this present challenges for vaccine trials? [Editor's note: The South African courts recently ruled in favor of national access to nevirapine.]
Life is not only full of surprises but also of contradictions. It is important to say this on record: South Africa has always supported the development of an AIDS vaccine as one of its major strategies, and this support came long before AIDS vaccines were fashionable. AIDS vaccines are something that has been etched in the minds of South Africans. They have always seen vaccines as the hope for eliminating HIV/AIDS, and they have seen a program to develop a vaccine as something they support.

SAAVI is supported by the government and ESKOM. There is no way—with this commitment and the time that has been invested in planning these trials—that the government will buy out of a process it has nurtured from the beginning.

So the fact that there has been controversy over nevirapine availability and toxicity [for prevention of mother to child transmission]—
That has nothing to do with vaccines. It will have virtually no impact. Government is updated quarterly about what is happening with vaccines. If they wanted this work to stop, or change direction, they have had the opportunity. But they have always given full support and encouragement.

Is the difference that the project has originated here, and the product is explicitly South African?
Partly. South Africans are not only patriotic but they are a little bit arrogant. We take our national pride very seriously. We like things that are South African. We are not isolationist, but we do like things that we have put our effort and participation into.

Is South Africa in a position to offer antiretrovirals to people who become HIV-positive during vaccine trials?
Yes. I think that is standard. I mean, South Africa offers antiretrovirals to prevent mother-to-child transmission.

Only in pilot programs.
That is a semantic issue. In principle, antiretrovirals are being used in South Africa all the time.

But researchers at nevirapine pilot sites have been told by the Ministry of Health to stop distributing nevirapine to other clinics that request the drug. In principle a clinical trial will not be out of phase with what is happening at the so-called pilot sites because it is a trial, a research project. It won’t be out of that kind of jurisdiction. A clinical trial, by definition, is equivalent to a pilot site. So there is no question about it.

What are your goals for SAAVI for next year?
There is only one goal at the moment. It is to try to start the Phase I clinical trial [of a vaccine based on the Venezuelan equine encephalitis virus vector] early next year and to make sure it runs smoothly. After that, other consequences will follow, and we will see whether we can begin to test other clades that are coming up. We need to make sure that we take the lessons from this trial before making the next step. We don’t start walking without crawling, and we need to crawl early next year—to get the capacity and infrastructure we need.

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