As one of the world’s biggest pharmaceutical companies awaits the approval of a malaria vaccine tested on thousands of infants in different African countries, questions on safety, efficacy and ethics linger, following the controversial deaths of a number of those who were part of the trial sample.

The UK-based pharmaceutical multinational GlaxoSmithKline (GSK) submitted the vaccine, RTS,S/AS01 to the European Medicines Agency (EMA) last July, and hopes that it will be approved for use against the malaria parasite, Plasmodium falciparum, particularly in Africa, where the disease is a major killer.

GSK is also hopeful that once EMA approves the vaccine, this will pave the way for a favourable policy from the World Health Organisation that will see malaria-prone countries come up with immunisation programmes that will lead to its widespread use.

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GlaxoSmithKline Biologicals in partnership with the Programme for Appropriate Technology in Health’s (Path) tested the vaccine on close to 16,000 infants aged between five and 17 weeks in seven African countries.

These included Malawi, where claims that the vaccine had caused the deaths of 47 infants during clinical trials surfaced. The project was bankrolled mainly by the Bill & Melinda Gates Foundation, which channelled the funds through Path. Path is an international NGO dealing with health issues in Africa and Asia, and has its headquarters in the US.

The EastAfrican sought answers from individuals and organisations both in the US and Kenya on the death claims and other emerging issues on the malaria vaccine.

While GSK admitted that children had died during the trials, it denied that the number was 47, and also dismissed claims that the deaths were caused by the vaccine.

“No, we do not recognise this figure,” said Rachel Cooper, GSK’s global external communications manager.

“Deaths in children under the age of five are not uncommon in sub-Saharan Africa, and unfortunately, they have also occurred in children enrolled in the RTS,S clinical trials.”

David Poland, Path’s senior communications officer in the organisation’s Malaria Vaccine Initiative (MVI) also confirmed that indeed, some children had died while others developed serious health effects (called Serious Adverse Events – SAE, which is any undesirable experience associated with the use of a medical product in a patient). Mr Poland, however, denied that neither the deaths, nor the SAE’s were caused by the vaccine under trial.

“There were deaths during the trial, but none was due to the vaccine. In many of the trial sites, the death rate was below the community average because enlisted children got quick, top-notch medical care,” said Mr Poland.

“During the course of the phase II studies, SAEs were also reported, which is normal for trials of this size. The important point is that none of them was caused by the vaccine.”

But as GSK, Path, WHO and other partners make plans to roll out the vaccine to hundreds of millions across Africa and in other tropical countries, they are yet to address issues raised by scientists on the MVI. For example, Dr Mae-Wan Ho and Prof Joe Cummins of the London-based Institute of Science in Society questioned whether proper ethics were observed during the trials, and doubted the efficacy of the RTS,S/ AS01 vaccine.

The two scientists said that the clinical trials of the malaria vaccines on infants raise serious concerns over the safety of not only the malaria vaccine under trial, but of vaccines in general that are administered in large numbers to the young and very young. They also argued that the effective implementation of existing measures had eradicated malaria from many countries without the use of vaccines.

“We have criticised this vaccine based on the unacceptably high adverse impacts on infants and children during previous clinical trials and its low efficacy levels,” said Prof Cummins.

According to the WHO, results from Phase III trials released in October 2013 revealed an overall efficacy of slightly over 50 per cent.

“The estimated overall efficacy was a 55 per cent reduction in the number of all malaria episodes during the first 12 months of follow-up,” said WHO. “However, the vaccine’s efficacy dropped to 47 per cent against severe, life-threatening malaria; when it was administered with other vaccines in 2012, the efficacy level stood at 33 per cent for all malaria episodes, and 37 per cent for severe, life-threatening malaria.”

But the scientists argue that this compares poorly with other vaccines such as those for measles or polio which are almost 100 per cent effective, raising questions on whether RTS,S/AS01 is good enough to reduce malaria infection among targeted groups in sub-Saharan Africa.

However, developers of the vaccine say that although it is not 100 per cent effective, it provides an additional remedy to existing anti-malaria campaigns.

“The sheer number of children affected by malaria means that the cases of the disease that the vaccine can help prevent is impressive, and that used alongside established interventions such as bed nets, it could have a significant public health impact in Africa,” said GSK.

This is also an argument voiced by Dr Bertrand Lell, the director of the Gabon-based Albert Schweitzer Hospital — where the bulk of the vaccine trials were carried out.

He is quoted in the media as saying: “There is so much malaria that a 50 per cent reduction would have a big impact on the disease and on the health of children... but because it is not a 100 per cent effective, the vaccine would have to be accompanied by other methods including mosquito nets and rapid diagnosis and treatment.”

James Kiarie, a senior lecturer at the University of Nairobi’s Department of Obstetrics and Gynaecology, said that while there are ethical issues with regard to the trials conducted on children, one has to weigh the benefits.

“The reason the vaccine investigators conduct the trials on children is because malaria affects mainly little children and pregnant women. It is better to conduct the trials on children rather than on the women to guard against ethical issues, which would be greater as this would put unborn babies at potential risk,” said Dr Kiarie.

But according to Hans Herren, the head of the US-based Millennium Institute, who once headed the Nairobi-based International Centre of Insect Physiology and Ecology (Icipe), a more integrated approach to control malaria is the best option.

“Why wait for a vaccine when we know what to do today? A more integrated approach would put the local people in charge and thereby create jobs and assure long term sustainability and success. Besides, it is very affordable,” said Dr Herren.

Another area of controversy are claims that the trials were sponsored by the vaccine manufacturer GlaxoSmithKline Biologicals, and that its employees made up a large proportion of the co-authors that gave the RTS,S/AS01 vaccine a clean bill of health.
According to Dr Ho and Prof Cummins, this posed “a potential conflict of interest.”

While Ms Cooper confirmed that the authors of the RTS,S studies include scientists from GSK as well as from other organisations, she, however, ruled out any possibility of conflict of interest.

“Scientific papers are peer reviewed by independent reviewers; besides, the authors and conference presenters are required to disclose to the publication or conference any financial interest that may pose a conflict of interest,” said Dr Cooper.

For example, Dr Joe Cohen, who co-invented RTS,S/AS01 serves as the vice president of R&D, Vaccines for Emerging Diseases and HIV at GSK Biologicals, and was one of the co-authors of two scientific reports on the phase II trials.

His report was published in the Lancet in 2001 and 2004. And together with other scientists, Dr Cohen had concluded in 2001 that the RTS,S/AS02 is “safe” and is “the first vaccine to show significant protection against natural Plasmodium falciparum infection.”

Further, in a 2004 assessment, he described the vaccine as “safe, well tolerated, and immunogenic,” and that it was “an effective vaccine against malaria is feasible.”

Dr Cohen also participated in the writing of the scientific article Long-term Safety and Efficacy of the RTS.S/AS02A Malaria Vaccine in Mozambican Children published in the Journal of Infectious Diseases. The article concluded that “immunisation with RTS,S/AS02A reduced the burden of malaria by approximately one-quarter” and that the results “strengthened the rationale for advancing towards phase III trials, aiming to register RTS,S/AS.”

It was also established that William Ripley Ballou — who had co-authored a similar scientific assessment report on the vaccine in the New England Journal of Medicine, was an employee of GlaxoSmithKline Biologicals and held shares in the parent company.

According to WHO, sub-Saharan Africa continues to bear the brunt of the global burden of malaria. In 2012, 80 per cent of the estimated 207 million malaria cases worldwide were in Africa. In the same year, 90 per cent of the estimated 627,000 global malaria deaths occurred on the continent.

The past decade however, has witnessed unprecedented progress in malaria prevention and control on the continent. Between 2000 and 2012, malaria mortality rates among children under-five declined by 54 per cent. During the same period, malaria death rates decreased by 49 per cent in the population at large.

To fight malaria, many approaches have been used across the continent including the use of insecticide-treated nets, sterilising mosquito larvae, and the use of artemisinin-based combination therapies.

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