Communities of practice
Brian Greenwood: “Living in exciting times”
29 Jun 2009
It was 1980 and Professor Brian Greenwood, a British researcher who had just taken over directorship of the UK’s Medical Research Council Laboratories in the Gambia, noticed something rather interesting.
Despite being much less well-off, people in this tiny West African country – and Guinea Bissau and Senegal as it turned out – used bednets far more regularly compared with the people he had worked with in northern Nigeria some years before.
“When I first arrived in the Gambia, I found that there was a tradition going back at least a hundred years of using bednets, and traders were going around on bicycles selling nets in the villages,” he says. “However, people didn’t associate them with preventing malaria.”
Indeed many nets were ornate and decorated, viewed as part of the furniture, and even transferred between families as part of dowries. They were as important for maintaining privacy as for preventing mosquito bites.
Interested in whether bednets were effective in preventing malaria, Greenwood and his team were shocked when they tried to establish what was actually known. As he explains, “We looked in the literature to find evidence that nets stop malaria and no one had ever done a proper trial to show this.”
His team, based at Farafenni in the Gambia, conducted a community randomised trial (1) that revealed untreated nets gave about 30% protection against clinical attacks of malaria. A subsequent large-scale trial (2) showed that if the nets were treated with insecticide (smaller trials had already been done in the lab) they could provide even more protection – preventing 37% of cases.
That trial was to have profound effects. Further trials led to a national insecticide-treated net (ITN) programme in the Gambia. ITNs are now a key part of the global strategy to control malaria and, by the end of 2010, 250 million bed nets are expected to be made available throughout the world’s malaria-endemic countries.
Modest about the achievement (he believes he probably should have looked at bednets a bit earlier), the trials that established ITNs as a fundamental malaria tool were just one of Professor Greenwood’s many contributions to controlling a disease that kills up to a million people, most of them African children, every year.
Greenwood also conducted the first trials (3) to determine just how many deaths severe malaria caused in the Gambia, and the first African trials of Coartem, the malaria drug that is now widely used as first-line treatment for malaria. He has also participated in malaria vaccine trials.
More recently, he has been involved in a major study on intermittent preventive treatment of malaria in infants, children and in pregnancy (4). He helped to establish the Intermittent Preventive Treatment of malaria in infants (IPTi) Consortium, a group of malaria researchers from Africa, Europe, the United States that is working to generate rigorous and compelling evidence to guide policy on IPTi. [An Institute of Medicine report (5) recently established that IPTi reduced mortality by about the same rate as bed nets.] He has advised on trials in Ghana, Tanzania and the Gambia.
“I will continue to work”
After 30 years in Africa, including a baptism of fire as a result of the Nigerian civil war, and at 70 years old, Greenwood has no intention of retiring. (He is supposed to work as professor of clinical tropical medicine for two days a week at the London School of Hygiene & Tropical Medicine, but admits working for seven.) “As long as I’m still enjoying it, people still want me to and I have a contribution to make, I will continue to work,” he says. “It’s difficult to step away when such exciting things are happening in malaria control.”
After working for 25 years in a tiny malaria community with no interest from the outside, he now finds himself in a massive global community that talks about malaria eradication. “I never thought I would be around to talk about malaria eradication. It’s just incredible really,” he says.” I don’t think elimination is around the corner but it’s not crazy to be talking about it now.”
There are many demands on his time. He still works with the Malaria Centre, a project he set up after returning to the UK in 1996. It brings together specialists in different disciplines, from economists and laboratory technicians to public health experts, to focus on malaria at the London School for Hygiene & Tropical Medicine. He directed the centre until 2006.
Plus, he is overseeing grants, including a new PhD training course for African malaria researchers. This so-called Malaria Capacity Development Consortium will train 20 PhD students. It is a metamorphosis from an earlier project, funded by the Bill & Melinda Gates Foundation, which provided funding for malaria research and 33 PhDs. The PhDs were eventually divided amongst several universities including LSTMH, the Liverpool School of Tropical Medicine and the University of Copenhagen, although students were based in Ghana, Malawi, Tanzania and the Gambia. 30 out of 33 of the postgraduates still work in Africa and many in research consortia on malaria in pregnancy, new insecticides and artemesinin combination therapies. Some are even directing their own major research projects within these groups.
The new project, which is funded by Wellcome Trust, will differ slightly. Students will earn PhD from universities in Africa rather than Northern institutions. That means money can be spent not only on students but on training supervisors, personal development officers and kitting up departments within universities, says Greenwood.
Not just malaria
But interestingly, malaria occupies just half of Greenwood’s time. Much is taken up with work on meningitis and in other research areas.
Indeed, Greenwood is about to start work on large-scale trials to discover whether a new meningitis vaccine is successful in stopping the transmission of disease altogether. He is working with a group called the African Meningococcal Carriage Consortium (MenAfriCar) with researchers across several countries, including Ethiopia, Chad, Nigeria, Niger and Mali.
Meningococcal infections, particularly the deadly bacterial forms, have been of great interest to Greenwood since he was based at Ahmadu Bello University in Zaria, Northern Nigeria in the seventies. Here, he found himself at the epicentre of one of the regular epidemics that blight countries from Ethiopia to the Gambia and Senegal. So common are these epidemics that the area is called the meningitis belt.
“It’s terrible. People are dying, there are thousands of cases and it’s very disruptive to everything,” he says. “Look at the fuss that is made of swine flu. Can you imagine what would happen if thousands of people were getting this disease and dying?”
He has worked on meningococcal drug resistance and developed a rapid diagnostic test to pick up the disease, which is still in use 30 years later. When new meningococcal polysaccharide vaccines became available in small amounts in the 1970s, he was one of the first to study their efficacy in Africa. Such vaccines were able to halt an outbreak – and have been used widely as a result. But what they cannot do is prevent epidemics.
Later trials of meningococcal polysaccharide/protein conjugates, which he carried out in the Gambia (6), revealed that only one of the two serotypes– named A and C – included in the vaccine was effective. While serotype C worked very well, and is used in widespread immunisation today, serotype A was not as immunogenic and so development of this vaccine was ditched.
The problem is, African epidemics are largely caused by meningococci belonging to serogroup A and precious little research into vaccines for this particular group means that epidemics still regularly take their toll in Africa. The latest claimed tens of thousands of lives in Northern Nigeria in June this year alone.
That is why work on a completely new vaccine is so exciting. A Gates-funded group, called the Meningitis Vaccine Project (MVP) has developed a serogroup A conjugate vaccine for use in mass vaccination campaigns in Africa. Greenwood has been an advisor to the group, which is fully aware that there is no commercial market outside Africa. It estimates that the project will need 250 million doses of conjugate A vaccine over 10 years to inoculate everyone up to 29 years of age. The MVP vaccine is about to be considered for pre-qualification at the WHO, and the first batches are expected to be made available in Burkina Faso by the end of year.
Greenwood’s job now is to work out whether the vaccine not only halts epidemics but stops people carrying the meningococcal diseases in droplets in their throats.
“We don’t know who is carrying the epidemic strain of meningococcus in the African meningitis belt, because there is very little data on that,” he says. “If we can show that the new vaccine gives long-lasting protection and stops people spreading the infection to each other, epidemic disease may then disappear.”
Responding to needs
Greenwood’s work on meningococcal disease is perhaps indicative of his approach to research. It came about by having to respond to the needs of people at field sites where he worked in Nigeria. Research into other diseases, including malaria, followed the same principle – a response to what was being seen on the ground.
He remembers that as a public health clinician, he was quite a different species from the biologists already working at MRC in the Gambia. In a rather run-down facility that was in danger of being closed down, he chose to focus on disease control.
“Our focus was more on interventions,” he says. “Not studying malaria parasites because they are very interesting, but how we can kill the wretched things.”
That meant first focusing on epidemiology; analysing what people in the area were suffering from. That ground-breaking research (7) for the first time revealed that as many children were dying from pneumonia as malaria in the Gambia. (Greenwood’s work revealed that Haemophilus influenzae type b (Hib) was a major cause of pneumonia in Gambian children too. That was a surprise because Hib had primarily been associated with meningitis only).
What was discovered then, is still not sufficiently understood today, says Greenwood. “The area that is really neglected is pneumonia. It kills more children than malaria and in a broader area but somehow the message that it is such an important disease has not managed to get through.”
UNICEF agrees that pneumonia causes almost a fifth of all deaths of under-fives worldwide and more than AIDS, malaria and measles combined. Still, the two types of bacterial pneumonia and meningitis – meningococcal and streptococcus – collectively received just 1.3% of overall R&D funding in 2007, according to the George Institute – see TropIKA.net article. (HIV/AIDS, TB and malaria received close to 80%.)
The Gambian pneumonia discoveries led to a move from epidemiology into clinical trials; Greenwood’s group started to test existing trial vaccines against the two main causes of pneumonia – Hib and pneumococcus (8). Along with the hepatitis B vaccine, which was also trialled, these were the first time such expensive vaccines had ever been used in poor parts of Africa. Deciding to do so was a tough call because many detractors believed it a waste of time and money to trial vaccines in countries that could never afford them.
Brian Greenwood remembers: “People said, ‘You are mad, how can you do research on such vaccines?’ It required some courage I guess, but I thought we shouldn’t be deterred by something like that.”
The results have been remarkable. Phase III trials of Hib conjugate vaccines contributed to the adoption of Hib vaccine in the Gambia, which has reported the gradual disappearance of the disease (9). The international vaccine group GAVI has since subsidised the introduction of the vaccine in many of the world’s poorest countries.
And today, various mechanisms have been created to pay for more expensive vaccines. Pneumococcal vaccines that will work in Africa are being paid for by a $1.5-billion international initiative called the Advanced Market Commitment (AMC), which was approved last month – see TropIKA.net news story. Under the AMC plans, rich countries will pay pharmaceutical companies to manufacture the vaccine for developing countries.
The process has, however, been slow. It was some 20 years before other countries followed the Gambia’s lead and adopted Hib vaccination. Similarly, ITNs are still not ubiquitous decades after research established their link to effectiveness against malaria.
But there are reasons to be optimistic, says Greenwood. Specialist groups that have advocated for Hib, pneumococcal and rotavirus vaccines – known as the ADIPs – have done a great job to make sure such time lags don’t happen again says Greenwood. (He is a member of the GAVI panel that directs the pneumococcal and rotavirus ADIPs and the Hib Initiative).
And the enormous momentum around malaria should help catch-up there too. “These are exiting times,” he says.
What are your priorities?
Immunology, pathogenesis and epidemiology of malaria and other infectious diseases including meningitis and pneumonia, all major contributors to mortality among children in Africa, training and support of young African scientists,
What have you achieved so far?
Demonstration of the effectiveness of insecticide-treated nets for control of malaria, which is now the cornerstone of malaria interventions throughout the continent, supported and financed by many donor agencies.
Primary studies on artemisinin-based combination therapies (ACTs), now widely adapted as first-line treatment for malaria.
Demonstration that malaria prophylaxis reduces child mortality. This is now being applied for intermittent preventive treatment in infants, children and in pregnancy.
Substantial contributions to trials of malaria vaccines, including the efficacious RTS,S vaccine.
Demonstration of how Haemophilus influenzae type b (Hib) infection can be eliminated by vaccination.
Large-scale clinical trials showing the potential for reducing child morbidity and mortality through use of pneumococcal conjugate vaccines.
Substantial contributions to the development of meningococcal vaccines.
1. Bradley AK, Greenwood BM, Greenwood AM, Marsh K, Byass P, Tulloch S, Hayes R (1986). Bed-nets (mosquito-nets) and morbidity from malaria. Lancet; 2(8500):204-207. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2873448
2. Snow RW, Rowan KM, Lindsay SW, Greenwood BM (1988). A trial of bed nets (mosquito nets) as a malaria control strategy in a rural area of The Gambia, West Africa. Trans R Soc Trop Med Hyg; 82(2):212-215. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3055456
3. Greenwood BM, Bradley AK, Greenwood AM, Byass P, Jammeh K, Marsh K, Tulloch S, Oldfield FS, Hayes R (1987). Mortality and morbidity from malaria among children in a rural area of The Gambia, West Africa. Trans R Soc Trop Med Hyg; 81(3):478-486. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3318021
4. Kweku M, Liu D, Adjuik M, Binka F, Seidu M, Greenwood B, Chandramohan D (2008). Seasonal intermittent preventive treatment for the prevention of anaemia and malaria in Ghanaian children: a randomized, placebo controlled trial. PLoS ONE; 3(12):e4000. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19098989
5. Institute of Medicine (2009). Assessment of the Role of Intermittent Preventive Treatment for Malaria in Infants: Letter Report. Available online: http://www.iom.edu/CMS/3783/48783/56178.aspx . Accessed June 2009.
6. Greenwood BM, Smith AW, Hassan-King M, Bijlmer HA, Shenton FC, Hughes AS, Nunn PP, Jack AD, Gowers PR (1986). The efficacy of meningococcal polysaccharide vaccine in preventing group A meningococcal disease in The Gambia, West Africa. Trans R Soc Trop Med Hyg; 80(6):1006-1007. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3603632
7. Wal RA, Corrah PT, Mabey DCW, Greenwood BM (1986). The etiology of lobar pneumonia in the Gambia. Bull World Health Organ; 64(4): 553-558. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3490924
8. Leach A, Ceesay SJ, Banya WA, Greenwood BM (1996). Pilot trial of a pentavalent pneumococcal polysaccharide/protein conjugate vaccine in Gambian infants. Pediatr Infect Dis J; 15(4):333-339 . Available from: http://www.ncbi.nlm.nih.gov/pubmed/8866803
9. Mulholland K, Hilton S, Adegbola R, Usen S, Oparaugo A, Omosigho C, Weber M, Palmer A, Schneider G, Jobe K, Lahai G, Jaffar S, Secka O, Lin K, Ethevenaux C, Greenwood B (1997). Randomised trial of Haemophilus influenzae type-b tetanus protein conjugate vaccine [corrected] for prevention of pneumonia and meningitis in Gambian infants. Lance; 349(9060):1191-1197. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9130939
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