In the context of innovative approaches for the prevention and cure of malaria in tropical countries, the development of a potent vaccine against the Plasmodium falciparum parasite represents a promising but still not achieved tool. Due to the lack of cost-effective treatments in most of the sub-Saharan countries and the thread of emerging resistances, a malaria vaccine is likely to be crucial in reducing both the morbidity and the mortality of this disease. However, unlike the well-known WHO driven eradication of the smallpox virus during the 1970s and various achievements of successful vaccination against the major childhood diseases such as measles, diphtheria, pertussis, tetanus and polio effective vaccination against malaria still remains a wishful goal. Nevertheless, recent success in basic research and clinical trials shed some light into the shade and encourages the STI to further strength its commitment in the development of a viable malaria vaccine.

At first hand, it sounds odd that after the first successful prove-of-principle experiment in mice with x-irradiated sporozoites by Dr. Ruth S. Nussenzweig (New York University, 1967) it took more than 40 years of research to achieve a 4 months lasting 60% effective vaccination against pre-erythrocytic stages of the parasite. However, even with an effectiveness of 60% the number of lives saved and the malaria symptoms significantly reduced within the most vulnerable group of young children in sub-Saharan Africa justifies our efforts in the development of a malaria vaccine. However, the development of a malaria vaccine is like a jigsaw puzzle and presents a difficult scientific challenge. Several factors account for the historic failure and may explain why at STI it necessitates a joint effort from several scientific disciplines such as parasitoloty, biochemistry, immunology and molecular epidemiology before one can think of the conduct of specifically designed clinical trials by the Pharmaceutical Medicine Unit.

From a research perspective, obstacles for the development a safe and effective malaria vaccine are manifold and stem from:

 

• Inadequate animal models
• A patchy understanding of the immune response
• A lack of safe and potent immune stimulative adjuvant
• An incomplete understanding of the functions of the thousands of proteins (and potential candidate antigens) expressed by the parasite
• A poor understanding of the relevant variable and conserved immunodominant and non-immunodominant epitopes for protection

In particular, the antigenic variability of surface proteins seems to be crucial for the parasite to evade the host's immune defense, and it’s obviously a disadvantage not only for the infected individual but also for the researchers aiming to design a vaccine. At first sight, it seems to be a logical consequence that some investigators revive the idea of using attenuated Plasmodium live stages as an all-in-one vaccine and could report a high protection against malaria under laboratory conditions. Unfortunately this approach appears technically difficult to pursue and unrealistic for scale up. Thus, the focus of malaria vaccine research at STI has been focused on selected antigens (whole proteins, synthetic peptides or carbohydrates) which are presented to the immune system – the so called subunit vaccine approach. This has also been chosen for the development of the aforementioned RTS,S pre-erythrocytic stage vaccine or PEV301 and PEV302, which are candidate components for incorporation into a multivalent virosomal vaccine during a joint project between Pevion Biotech Ltd. and the STI. A bivalent vaccine candidate consisting of PEV301 and PEV302 is currently tested within the PMAL03 Phase Ib trial at the Bagamoyo Research & Training Centre (BRTC) of the Ifakara Health Institute (IHI), Tanzania.

The conduct of clinical trials in accordance to internationally accepted guidelines and ethical principles for the development of new drugs in resource limited countries demands for a thorough knowledge of the local circumstances and regulatory requirements. This holds especially true for the conduct of a malaria vaccine trial in sub-Saharan Africa. Ensuing the early laboratory research and animal testing for vaccine candidate needs to be assessed for its safety under defined conditions of clinical trials – first, in non-immune volunteers (Phase Ia trials), and then in semi-immune volunteers of malaria endemic countries (Phase Ib trials). Extended, Phase II and Phase III trials involving thousands of volunteers at various clinical sites that are followed-up, upon confirmation of the vaccine's safety and immunogenecity. However, albeit the different size and goals of the early and late phase trials, there are certain characteristics that may render challenging any stage of the malaria vaccine development.

Attention needs to be paid to the safety of the volunteers representing the focus group for the future malaria vaccine – mostly young healthy children. This has also been considered and elaborated in the study protocol for the aforementioned PMAL03 trial carried out in Tanzania. Though the preceding Phase Ia trial did not raise any safety concerns, the malaria vaccine had been applied first in 10 healthy adult men to mitigate the risk for the 40 children vaccinated in a staggered approach thereafter. As a preliminary result of the ongoing trial, it should be pointed out that the vaccine proves to be safe and that the volunteers show a very good compliance. However, this is not always the case and can surely be attributed to the experienced study team at the BRTC of the IHI.

That being said, one might ask what characterizes a successful study team, what makes a clinical trial protocol comprehensive and adequate, what constitutes an informed consent applicable to children volunteers and what are the main difficulties to carry out a vaccine trial in sub-Saharan countries. Most importantly, the study has to account for the special needs of children volunteers. Vaccine trials are complicate and comprise numerous of detailed clinical and laboratory assessments lasting over several months or even years, whereas in most cases children or infants are too young to understand the trial and to assess the possible risk versus the possible benefit. And even their parents or caretaker might not fully understand all implications of the trial when giving their consent for the child's participation. Thus, for the PMAL03 trial an adequate and understandable volunteer information had been written and translated into Swahili, the local language. Still, the investigator has to verbally provide all explanations about the trial with a thorough understanding of the person's educational background and possible concerns about a malaria vaccine trial. People might be me, for instance, concerned about the confidentiality of HIV test results and exposure to the community, giving signatures, photos taken or the blinding within a controlled trial. These topics need to be adequately explained and enough time has to be given to each participant to rethink their decision whether or not to allow their child to participate in the trial. Thus, for the PMAL03 trial, each parent or caretaker had been requested to evaluate the information presented during 2 days before taking any decision. This is of special importance to allow a family or even community based decision on the possible participation of the child.

Moreover, broad vaccination programs are yet disputable and not without any doubts from a scientific and public health point of view. Possible loss of the protective immune status that has been acquired over many years in an endemic area is still a major concern, therefore representing a potential threat to the individual and to the whole community. This might occur if a continuous antigenic stimulation ceases after successful malaria vaccination and could render the vaccenees more vulnerable to malaria due to a reduced semi-immunity. Therefore, a close and lengthy post-vaccination follow-up of each vaccenee is an indispensable requisite of a malaria vaccine trial in disease endemic areas with a high transmission rate. Effects on malaria transmission or the long-term dynamics of immunity should always be considered for such trials.

Obviously, special abilities and experiences are needed to enable the local study team a smooth and successful conduct of the trial. All PMAL03 team members at the site, the nurses, investigators, coordinators and the mobile team have to adapt their experiences gathered during clinical trials on new drugs to the special requirements of a malaria vaccine trial. By analogy to the testing of new drugs where the effect and cure is perceived within a short time frame, a vaccine might also be considered as an absolute protection – which is not the case. Understanding the fact that the protective effect of a malaria vaccine is rather gradual and ranges from an elevation of all malaria symptoms to the possible failure for an individual. Thus, especially in large vaccination programs, it is up to the community health workers (mobile teams) to inform each family as well as the village community that the positive effect of a malaria vaccine does not protect the vaccinee from the infection but aims at a reduction of malaria symptoms and a possible control of transmission.

Besides the operational and technical challenges faced during a trial in rural areas, it has already pointed out that social and community based aspects constitute further topics which need to be addressed before the launch of the trial. For the PMAL03 trial we had to take measures for:

 

 

• A consistent follow-up of the volunteers over an extended follow-up period of 2 years to capture enough efficacy endpoints and ensure the volunteers safety
• A thorough understanding of the perception of the disease within the community
• A recognition of local traditions and social norms (1.-3.)

1. young women are often denied autonomy, their children's participation in research is therefore highly liable to be exploited
2. often it's the father to decide on the child's participation
3. the community leader has to be asked for assent; however, his decision should not override the individual's case

• A good interpersonal relationship between the staff and the volunteers
• To adequately explain why larger quantities of blood samples are needed for the assessment of the immune reaction (more than for pharmacokinetic samples in drug trials)

Basically, one has to respect the community's and the individual's concerns about the trial and has to be aware of the fact that people put their trust and high expectations in our work. This is of special importance since each volunteer will undergo through an in-depth medical assessment and possibly receive first-line treatment over a period of 2 years – which is usually not the case in rural areas. Thus, one might have to further explain why only some children are selected from a village and others are not or are even denied to participate after the preliminary health assessment.

Another challenge within the PMAL03 trial has been the implementation of the double blinded, controlled set-up. To avoid any bias from the investigator being aware about which vaccine (the malaria vaccine or the comparator vaccine) has been applied, an impartial vaccination officer had been assigned to the application and documentation of the vaccination procedure. Moreover, an adequate comparator vaccine (Inflexal®) had been chosen to enable a "controlled" conduct of the PMAL03 trial, which is respected as the Gold Standard in clinical development. However, unlike many drug trials there is no such Gold Standard available and for ethical reasons a vaccination of the control group with a placebo had been ruled out. Thus for the control group, a vaccine has been chosen to match the same basic virosomal structure, in addition to be functionally unrelated to the investigational vaccine but still providing some benefit. Due to the double blinded set-up, no information regarding the immunogenecity and tolerability of both vaccines, the investigational malaria vaccine or the comparator vaccine is available to date and will not be revealed before the end of the PMAL03 trial by mid 2009.

 

So far, we were pleased to note that that there is the high compliance by the volunteers and that no vaccine related Severe Adverse Event has been detected. Furthermore, the bridging between cultures, the implementation of a rather complicate malaria vaccine trial in a rural setting, as well as sharing the expertise have been successfully achieved within the PMAL03 trial at the BRTC of the IHI in Tanzania. 

 

Dr. Hermann Garden

 

back to mainpage