Vaccine trial in India: AIDS vaccine no guarantee to prevent infection

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THE HINDU

Thursday, Nov 21, 2002

AIDS vaccine no guarantee to prevent infection

http://www.hinduonnet.com/thehindu/seta/stories/2002112100030200.htm

By R. Prasad

Indian vaccine will have only cell-mediated immune response and not

neutralising antibodies. It may not protect against infection but will stop

the progression to disease state and also reduce transmission.

AIDS vaccine will not use weakened or killed whole virus. Instead DNA, genes

or proteins will be used to minimise the risk of infection.

THE HUMAN Immunodeficiency Virus (HIV) juggernaut infects nearly 600 people

every hour and kills nearly three million people a year. Unfortunately, the

scientific community is chasing a mirage in its quest to find a vaccine.

The latest round of trials in various countries to find a potent vaccine is

just a testimony to their untiring efforts. It is against this backdrop that

International AIDS Vaccine Initiative (IAVI) along with other Indian

scientific institutions is gearing itself to test a vaccine to contain the

disease. Animal studies would begin early next year. If everything goes fine

a reliable vaccine should be available in 7-10 years' time.

But there are many ifs and buts to it before the scientists' dream is

realized. " We don't have answers for everything. Waiting for all the answers

before developing a vaccine will mean a delay of 50 years. Maybe more, " said

Vijay L. Mehra, Program Director, Applied Vaccine Research, IAVI. But IAVI

is in no mood to wait any longer as it is convinced that a preventive

vaccine has to be made available urgently.

In the first place what is it that makes HIV so difficult to conquer? To put

it in a nut shell the virus attacks the very immune system (helper T-cells

also known as white blood cells) that kills any foreign body. Once inside

the white cell, the virus multiplies and finally kills the white cells. The

process continues till the number of white cells drops beyond a level when

the disease (AIDS) manifests and finally to death. Moreover, the virus is

continuously changing itself to avoid detection by the immune system. The

genetic variability in the virus has led to distinguish several HIV-1

families and subgroups. According to these genetic differences, several

subtypes have been definedThe need to look for India specific vaccine arises

due to the predominance (nearly 90 per cent) of subtype C. Fine, but why did

IAVI choose India for testing subtype C vaccine when it is prevalent in

other countries too? " We based it on certain parameters — AIDS is a big

epidemic in India, the country has a strong scientific strength in this

field and has done enough homework, has the potential to manufacture the

vaccine once it is proven viable and has more informed population and NGOs.

But importantly the government's impetus to develop a vaccine played an

important part, " said Mark Chataway, Team Leader, India for IAVI.

Once developed it could be used in other countries with similar subtypes.

" The possibility can be checked only when a vaccine becomes available as

minor variations, within a subtype exists " Dr. Mehra cautioned.

Reinventing the wheel?

What is the need to start from the scratch to develop a subtype C vaccine

when a couple of trials for other subtypes have already reached phase III?

" A proven vaccine will provide the proof of concept to develop similar ones

for other subtypes, " explained Dr. Mehra. Simply put it translates to time

saved — a vaccine may be ready in say two years time compared to more than 7

years.

So if the time saved is significant then why does IAVI go about testing

vaccines simultaneously and not wait for results of other trials? " It is

true that we will stand to gain on time. But what if results of the on going

trials are not favourable? " asked Jean-Louis Excler, Director, Medical

Affairs, IAVI, India. A promising vaccine will go on phase III trial in

Thailand early next year. " But the results of this will be known only in

2005-2007. We can't afford to wait for this result before starting Indian

vaccine programme, " Dr. Jean-Louis asserted.

Finally the issue of one subtype changing to another though not inside the

human body and two subtypes combining to form recombinant subtypes are

known. " The only way to prevent this is to have a vaccine in place at the

earliest, " Dr. Mehra reiterated.

Parts mimic the whole

All AIDS vaccines under trial are based on the cardinal principle that parts

of the virus (sub-units) used represent the whole. This is the technology

(recombinant bio-technology) used in the case of hepatitis B vaccines. The

parts taken from the virus are supposed to mimic the whole virus and ready

the body's immune system to recognize the virus by identifying these

portions found on it. There is little fear of the vaccine causing disease,

as critical parts of the virus are not taken.

But in the first place how does one identify the critical and non-critical

parts of the virus? This identification becomes all the more important as

certain parts of the virus are constantly changing. " Some regions on gp 120

(outer surface protein used by virus to attach to a cell) are variable and

some hyper variable. Fortunately we have some regions that are conserved and

hence stable. So a vaccine uses this conserved region, " Dr. Mehra explained.

The genes or proteins selected are modified before being injected. Vectors

either bacterial or viral are used to introduce the HIV genes or proteins as

vaccines. Naked DNA vaccine requires no vector. The DNA used is not a virus

by itself though it has the capability to multiply (in limited numbers) and

produce proteins once inside certain cells. The DNA is removed from the body

in three weeks time. DNA vaccine is used for priming the immune system.

The Indian Modified Vaccine Ankara (MVA) will use of six proteins. " These

are cloned and modified to make them ineffective in causing disease.

Moreover, even if they combine they cannot form the virus as four-five

proteins would still be missing, " Dr. Mehra highlighted.

Attacking the virus

The strategy to attack the virus in a vaccinated person is two pronged.

First line of defence is to neutralise and prevent the virus from attaching

and entering the cell. It is called `neutralising antibody.' The neutralised

virus becomes ineffective. The second line of defence is to kill the virus

so neutralised. This is achieved by immune system's killer T-cell response.

This works on the principle of prime-boost concept (prime prepares the

immune system while boost improves the response of the immune system against

the virus) and is tested in several countries.

IAVI does not have at the moment such a trial going on. The vaccine

strategies developed so far are designed to induce strong killer T-cell

response (cell-mediated immunity). The vaccine trial planned for India is

designed to induce strong cell-mediated immune responses, not neutralizing

antibodies. " Though research shows the need to have either neutralizing

antibody or killer T-cell response, it is ideal to have both in the

vaccine, " Dr. Mehra commented.

IAVI's logic of using only a cell-mediated immune response (killer T-cell)

is based on observations that gp120 is able to neutralize HIV grown in

laboratory conditions but not the virus circulating in the community. " So

the efficacy of such a vaccine is doubtful and if any may be low, " Dr. Jean

explained.

In the absence of neutralising antibodies vaccines may not protect against

infection but only against progression to disease and also reduce

transmission. This is achieved as the vaccine is able to recognize virus

infected cells and to kill them before they produce new viruses.

Elusive mucosal immunity

If not much is known about the efficacy of neutralizing antibody, very

little is known about the immune system of the mucosal surfaces of the

genitalia.

This lacuna in our knowledge becomes serious as nearly 80 per cent of HIV

infection is through sexual transmission. According to Dr. Mehra antibodies

present locally in the mucosal surface will help fight the virus at the site

of entry at the very first instant. Unfortunately, neutralizing antibodies

are not present in mucosal surfaces.

" It is difficult to produce a vaccine that stays there locally forever. Even

a DNA vaccine is removed in three weeks'time and only goes to build the

immune response, " she said. " A vaccine cannot produce mucosal immunity if it

is predominantly generating T-cells response. "

Dr. still pins his hopes on the positive outcome from the on-going

trials. " There is some evidence that immune responses induced at the

systemic levels can to a certain extent be detected in mucosal secretions

and cells. So a vaccine inducing systemic immune responses can also be of

major interest in protecting against sexual transmission, " he assured.

" There is considerable effort to develop a vaccine that could be

administered by mucosal route. "

Issues before us

First and foremost is the question of knowing the HIV incidence rate in

India. At present only the prevalence data is available and incidence rate

is not known. Knowing this is essential for understanding the feasibility of

the phase III efficacy trial. Scientists are not quite sure if the vaccine

will turn out to be prime-boost bundled into one making a separate boost

vaccine redundant or it will end up as just a boost vaccine.

If the latter is the case then a prime is required. InThis has not been

identified though.

It remains to be seen how IAVI conducts phase III trial (to know the

efficacy) involving volunteers exposed to the virus through " high-risk "

behaviour. India is already a witness to two clinical trials where

procedures and ethics were thrown to the wind.

And finally top priority is accorded to get a vaccine (even if partly

efficacious) off the block. Hence cost, suitability to tropical climate and

mode of administration have taken a back seat.

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