2,000 children to get experimental malaria vaccine_Nature / BBC

Tue, 22 Jul 2003

Malaria kills millions of African children yearly. For many decades malaria vaccines have been sought but have been dismal failures.

NATURE and BBC report that a vaccine experiment will be conducted in 2,000 children in Mozambique–even though the vaccine’s safety has only been tested in adults in small phase I trials.

The sponsors are GlaxoSmithKline and the Malaria Vaccine Initiative (MVI, funded by the Gates Foundation). In addition to the malaria parasite protein, the vaccine contains “a fragment of hepatitis B” and an adjuvant. Nature reports that the vaccine trial sponsors (GSK and MVI) claim that in the adult tests the vaccine (RTS,S) “protected up to 71% of adults from being infected with malaria.”

However in the next paragraph the article notes that Melinda Moree, director of the MVI admits that “Chances of success are slim. We’re going to hear more about failures than successes….Even negative results move us quite a way forward,’ she says.”

BBC reports that in the adult trial the vaccine’s protective action wore off after two months.

The experiment raises serious ethical concerns that need to be addressed before 2,000 children are exposed to an experimental vaccine that the sponsor admits is likely to fail:

1. What are the subjects’ parents told about the vaccine?

2. Since the vaccine has not been tested in children before, its safety in children has not been assured. Therefore this is essentially a phase I safety trial. Why then, are 2,000 children being exposed before its safety in children has been established?

3. If the efficacy rate in the small phase I adult trials was 71% what led the sponsor to state that the vaccine’s “chances of success are slim”?

4. What were the negative findings of the adult trials?

5. What is the adjuvant used with the vaccine?

6. What is the adjuvant’s toxicity in humans–since it is not licensed in the US?

7. What is the toxicity of the portion of the Hepatitis B virus that is included, given that France halted its countrywide Hepatitis B vaccination program several years ago due to serious neurologic side effects in a minority of recipients?

8. Since the vaccines protective effect of the vaccine in the adult safety trials wore off after just two months, does the sponsor and those conducting the trial anticipate inoculating the children every two months?

9. If so, what evidence is there that multiple shots are safe? Shouldn’t children’s exposure to an experimental vaccine be guided by precautionary measures? Phase I (vaccine safety trials) do not test multiple inoculations.

10. What is the ethical justification for a "trigger happy cowboy approach?" Should scientists be allowed to take risky leaps without adequate safety data and expose 2,000 children to an experimental vaccine that the sponsor admits has "slim" chances for success?

Vera Hassner Sharav, President, AHRP Meryl Nass, MD, Board member, AHRP

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http://www.nature.com/nsu/nsu_pf/030707/030707-4.html

Two thousand kids to get experimental malaria jab
Largest ever test of malaria vaccine to begin in Africa.
9 July 2003
Tom Clarke

Malaria kills one million people a year in Africa.
© WHO

The most advanced test of a vaccine against malaria ever conducted in children begins in Mozambique next week. The hope is that immunization will become a primary weapon in the fight against malaria, which kills 1 million Africans each year, most of them toddlers and babies. Currently, drugs – to which resistance is rapidly developing – and protections like bed nets are the only ways to control the disease.

Two thousand children under five will take part in the trial, funded by the Malaria Vaccine Initiative (MVI), an independent organization based in Rockville, Maryland, which coordinates international efforts to develop malaria vaccines, and drug giant GlaxoSmithKline. “This is the largest malaria vaccine trial carried out in Africa to date,” says Pedro Alonso, scientific director of the study’s base, the Manhiça Health Research Centre in Mozambique.

Tests with small numbers of volunteers have satisfied researchers that the candidate vaccine – called RTS,S – is safe. The next stage, a phase 2 trial, will now ask whether the vaccine actually prevents malaria in children. Results should be available in 18 months.

RTS,S consists of a protein found on the surface of the malaria parasite at the stage when a mosquito’s bite injects it into the human body. It also contains a fragment of the hepatitis B virus, too little to cause the disease, but large enough to goad the body’s immune system into recognizing the malaria fragment.

A chemical mix called an adjuvant is the final ingredient. This tricks the immune system into mounting a strong immune response to the vaccine, helping it to remember the crucial parasite protein. In tests in the Gambia, RTS,S protected up to 71% of adults from being infected with malaria. If the vaccine has similar success in children it must then pass further tests in babies. Those under a year old are excluded from this trial for safety reasons but are at the highest risk of dying from malaria.

Chances of success are slim, admits Melinda Moree, director of the MVI. Only one of 80 current malaria vaccine concepts is estimated to succeed, she explains: “We’re going to hear more about failures than successes.” But a clinical trial is the only way to find out what approaches do and don’t work. “Even negative results move us quite a way forward,” she says.

That RTS,S is in the most advanced stages of testing doesn’t mean it is the best candidate vaccine. It has been in development since the 1980s and has the backing of a large company, says Adrian Hill at the University of Oxford, UK.

Hill’s team is working on a different approach using modified viruses to carry malaria genes into the body; initial results are promising1. Around nine other candidate vaccines are also in safety trials this year.

References McConkey, S. J. et al. Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccina virus Ankara in humans. Nature Medicine, published online, doi:10.1038/nm881 (2003).

© Nature News Service / Macmillan Magazines Ltd 2003

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http://news.bbc.co.uk/2/hi/health/3054734.stm
BBC
Malaria vaccine trial begins

Scientists hope they are moving closer to preventing deaths from malaria with a trial to test a vaccine in children.

The mosquito carries the malaria parasite Two thousand children aged one to four will be given the vaccine in a study to measure how effective it is at preventing infection.

About 3,000 African children die of malaria every day.

A number of vaccines are being developed to prevent deaths and illness, but research into this particular vaccine, created by pharmaceutical company GlaxoSmithKline, is the most advanced.

“Each year, a million more children vanish from the face of the earth because we don’t have a vaccine.” Dr Melinda Moree, Malaria Vaccine Initiative.

Trials in Europe, the US and Gambia and Mozambique have already suggested the vaccine is safe and effective for adults.

This latest research, which will be carried out in an area where malaria is endemic, will also check the vaccine is safe for small children to take.

The children will be monitored for up to 18 months, longer than previous trials of the vaccine, to see if they develop the disease.

Prevention

In previous short-term trials of the vaccine, its effectiveness has appeared to wear off after two months. It is hoped that its protection will last longer in children.

If the trial is successful, further research will be needed.

Researchers estimate it could be between five and eight years until the vaccine, RTS,S/AS02, is available, even if the trials are successful.

When a mosquito bites, it transmits an early form of the malaria parasite called the sporozoite into the bloodstream.

From there, it moves to the liver, where the full parasite develops.

Researchers hope that by interrupting the life cycle of the parasite at the early sporozoite stage, it will be possible to arm the immune system against infection.

The vaccine is made from a surface protein from the sporozoite.

This is then combined with two substances which will trigger the immune system to attack.

Delay

Dr Pedro Alonso, who is heading the study in Mozambique, said: “We are looking at whether it could be delivered early in life in a programme where it could be delivered to young infants.”

“Our team is committed to finding ways to prevent malaria from remaining the number one killer of Africa’s children.

“This trial is an important contribution to that effort and brings us that much closer to the goal of immunising children against malaria.”

Dr Ripley Ballou, of GlaxoSmithKline, who has been involved in the development of the vaccine, said: “We will be looking to see how many children become infected, do they develop anaemia, or other complications of malaria.”

Dr Melinda Moree, director of the Malaria Vaccine Initiative which is backing the Mozambique research, said: “For each month of delay, 120,000 children die of malaria.

“Each year, a million more children vanish from the face of the Earth because we don’t have a vaccine.”

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