THE BURDEN OF ENDEMIC INFECTION – THE MALARIA VACCINE IMPLEMENTAION. Recent variations in population density, mobility, and social constructs, along with alterations in the global climate, ecological circumstances, and the closeness (proximity) of humans to animal reservoirs for previously confined infectious agents, the concept of new infectious agents emerging in human populations and spreading rapidly around the world is no longer new or novel. In confronting newly emerging diseases, vaccines maybe looked to as the most promising perspective of defense.
The ddevelopment of vaccines today faces a number of significant challenges although significant improvement has also be seen among scientist since the publication of Edward Jeanner in 1879. There exist tremendous public health needs to address major well-known pandemic diseases, including acquired immunodeficiency syndrome (AIDS), and tuberculosis for which maybe a budrden and for which natural immunity does not provide a helpful guide for vaccine development. Only until 2018 there exist Malaria vaccine after such a long efforts.
Furthermore, there exists a need to confront effectively newly emerging and re-emerging diseases, ranging from the well-known, but constantly changing, threats from influenza pandemics to the appearance of Malaria and zoonotic infections such as the coronavirus that causes severe acute respiratory syndrome (SARS) outbreak especially in the Asia pacific..
In this regards, our focus will explore malaria and its current vaccine RTS,S/AS01 or Mosquirix. Effective and safe vaccine against malaria has since a long time posses as a real challenges for it development. Although persistent efforts have been tried to find various vaccines for the disease. Hence numerous vaccines are available on trial but among them that seems to prove effective is the current RTS,S/AS01 vaccine also known as mosquirix.
HOW DO VACCINES WORK?
When inactivated or weakened disease-causing microorganisms enter the body, they initiate an immune response. This response imitate or mimics the body’s natural response to infection. But unlike disease-causing organisms, vaccines are made of components that have limited ability, or are completely unable, to cause disease.
When vaccines enter the body, the immune system of the human body is triggered or promoted to identify such weakened disease causing organism as a foreign body (antigen). The components of the disease-causing organisms or the vaccine components that trigger the immune response are known as “antigens”. These antigens trigger the production of “antibodies” by the immune system In otherwise, the body then produces antibodies (which are disease fighting substances) to attack the weakened the disease causing microorganism (called the vaccine). This triggered immune action is registered and form a memory in our body, the next time the real disease causing organism enter the body this time round which is capable to causing diseases, base on the memory of the previous weakened microorganism (prototype of the real) called the vaccine, such real disease causing microorganism is identify quickly and the body’s system fight and eliminate the infection before it can cause harm to the Body hence protecting the individual. However, In very young children, the immune system is immature and less capable of developing memory. In this age group, duration of protection can be very short-lived for polysaccharide antigens.
THE MALARIA VACCINE
Today the term ‘vaccine’ applies to all biological preparations, produced from living organisms, that enhance protection (immunity) against disease and either prevent (prophylactic vaccines) or, in some cases, treat disease (therapeutic vaccines). In other wise, vaccines act as soldiers to help fight or provide protection against diseases. Vaccines are administered in liquid form, either by injection, by oral, or by intranasal routes.
Malaria is caused by Plasmodium falciparum parasite found in female anopheles mosquito. A Malaria Vaccine Technology Roadmap (MVRM), developed by more than 230 experts representing 100 organizations from 35 countries, has set out a strategic goal to develop a malaria vaccine by 2025 that would have a protective efficacy of more than 80% against clinical disease and would provide protection for more than 4 years. The MVTRM asserted to seeks to develop and license a first generation malaria vaccine by 2015 that has a protective efficacy of more than 50% against severe disease and death, and lasts for at least 1 year. It is against this backdrop that the current malaria vaccine was approved for use by WHO in three selected Africa countries (Ghana, Tanzania and Malawi) due to the endemic nature of the disease burden in these areas for which previous clinical trials were conducted.
It’s prudent to mentioned that, although pneumonia and severe diarrhoeal disease remain two major causes of child mortality worldwide according the World Health Organization (WHO), Malaria has caused many death which includes maternal death and infant mortality (children under five years) in the tropics especially in sub sahara Africa. However, could the vaccine Mosquirix meet the Malaria Vaccine Technology Roadmap promises and projection?.
Vaccine efficacy is elaborated by the WHO to refer to measures direct protection (i.e. protection induced by vaccination in the vaccinated population sample). In otherwise, vaccine efficacy may be defined as a measure of the proportionate reduction in disease attack rate between a control group that is vaccinated against the infectious disease under study and the group vaccinated with the candidate vaccine (those who do not have the disease).
It explains the number of people the particular vaccine under consideration may protect if an X number of people have or is exposed to a disease condition. Usually, efficacy is measured in percentage. For example; if a vaccine is labelled at an efficacy rate of 30%, to put this in perspective, it means that when you take 10 people who are to be infected with Malaria, the particular vaccine is capable of protecting 3 individuals among the 10 cases/individuals.
Vaccine efficacy varies according to the type of vaccine and the manner in which the vaccine antigen (protein/enzyme) is processed by the immune system. Vaccine efficacy may also vary between different populations. However, to be generally acceptable, the efficacy of licensed vaccines ranges from above 70% to almost 100% (See Figure 1). In other words, vaccines could be expected to reduce the attack rates in the vaccinated population by 70-100% compared to the attack rates in the unvaccinated population.
In the case of Mosquirix, efficacy was pointed out by the pivotal study (the final study conducted which trigger the vaccine adoption decision) as 39%. Which was below the recommended threshold. This means that the malaria vaccine Mosquirix can prevent about 4 in 10 cases of malaria and about 3 in 10 cases of life-threatening, severe malaria over a four-year period space. In addition, the 4-dose vaccine schedule reduced severe malaria by 31.5% in 5-17 month age group , with reductions also seen in malaria hospitalizations, all-cause hospitalizations and the need for blood transfusions. Among children aged 5–17 months who did not receive a fourth dose of the vaccine, the protective benefit against severe malaria was lost, highlighting the importance of the fourth dose of this mosquirix vaccine to maximise its benefits.
RTS,S/AS01 or MOSQUIRIX vaccine was acknowledged not to be effective among the younger infants less than 5 months hence the malaria vaccine did not work sufficiently well to justify its further use in this age group.
In the light of this, could this efficacy rate of 39% be acceptable for implementation of vaccination exercises in children in Ghana relative to efficacy rate of previous and most developed early vaccine for other public health diseases?
The pivotal phase 3 clinical trial study clearly pointed out that, while the study is under review for scientific opinion at the time of publication in 2015 by Committee for Medicinal Products for Human Use (CHMP) via the European Medicines Agency Article 58, Malaria-endemic countries for which Ghana is included will need to decide whether to license and use RTS,S/AS01 (Mosquirix) or not as well as deciding on use schedule. It’s again worth mentioning that the results of mosquirix vaccine phase 3 trial is only to help for making and guiding decisions and, to adopt it with it potential to prevent cases of malaria. Which means national authorities have a burden of responsibility to carefully ascertain the study and figures presented as to whether it’s strong enough to illicit the necessary protection for the greater good of the affected population.
This then resonate another question; Could the adoption of the vaccine and it implementation base on glaring efficacy be regarded as a hasty adoption for implementation?
Further more, the authors of the pivotal phase 3 trial study pointed out that the vaccine could serve as a potential contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission.
The benefits of vaccination are indisputable. Just like any pharmaceutics drugs, there are associated effects with vaccines as well. Immunization has had one of such valuable impacts on health. Vaccines prevent death, illness and/ or disability. But reasons of the immune reactions that they induce, vaccines can cause some discomfort. The vast majority of adverse events associated with vaccines ranges from severe, minor and transient. These are typically pain at the injection site, or mild fever. More serious adverse events occur rarely. Some serious adverse events may occur that their risk cannot be accurately assessed due to the reason that, individuals may be sensitive to some components or trace elements in some vaccines, such as antibiotics, or gelatin or base on circumstantial cases. In contrast, the cause of rare adverse events is usually unknown. It is believed that rare and severe adverse events are associated with individual differences in immune responses. In the case of Mosquirix, adverse effect associated with the study was about a quarter of the children involved (that is 15,461 were involved in the study) in the pivotal phase 3 trials and only 0·3% (approximately 12 children of the associated quarter) were judged to be related to the vaccine. However, the study also pointed out that the signiﬁcant imbalance exist and remain in cases of meningitis in children vaccinated at the age of 5–17 months between the RTS,S/AS01 and control groups reported. Five new cases of meningitis were also noticed and recorded from month 21 until the end of the trial in children in the RTS,S/AS01 groups, but none occurred in the control group; two of the ﬁve new cases occurred in children who had received the booster dose of RTS,S/AS01 and three in children who had received the control meningococcal vaccine. Among children in the older age group, there were reported and increased risk of febrile seizures within 7 days after any of the vaccine doses. And among the younger infants, this risk was only seen after the fourth dose although there seems to be no long-lasting consequences due to any of the febrile seizures.
The increase in meningitis cases among the children observed for such condition, were quite difficult to be understood by the researchers, the authors pointed out. The effect of mortality of the vaccine mosquirix could not be adequately assessed in the Phase 3 trial due to the very low overall mortality in the trial setting. Hence there need to ascertain whether the excess cases of meningitis and cerebral malaria, identified during the Phase 3 trial, are causally related to RTS,S vaccination or not. The pilot implementation programme therefore could also be regarded as another form of experimentation or trial which may help generate critical evidence in 3–5 years’ time to enable decision-making about the potential wider scale use of the vaccine. A worth thinking about is, after the four years period of the pilot implementation, will the vaccination programme committees of these three pilot countries be stopped for assessment to be carried out whether the vaccine seems to be effective or not?
The mosquirix clinical trial was sponsored and funded largely by GlaxoSmithKline(GSK) Biologicals SA and in part by PATH MVI. While there seems to be a conflict of interest and an issue of ethical concerns by virtue of funding the drug research, GSK serves as sole manufacturing agency and distributor of the RTS,S or mosquirix vaccine.
In the light of this, could GSK Pharmaceuticals have interest in the vaccine development although efficacy proves to be below 50% even as promised according the Malaria Vaccine Technology Road Map? This and the other questions above needs to be critically assessed.
EXPLORING THE STAGES OF VACCINE DEVELOPMENT
Every vaccine goes through various phases of development. The general development cycle or stages of a vaccine are:
- Exploratory stage
- Pre-clinical stage
- Clinical development
- Regulatory review and approval
- Quality control
Clinical trials are regarded a critical source of data for decisions around the development of vaccines, drugs and other medical interventions. They are carried out in several phases. Clinical development is a three-phase process. During Phase I, small groups of people receive the trial vaccine. In Phase II, the clinical study is expanded and vaccine is given to people who have characteristics (such as age and physical health) similar to those for whom the new vaccine is intended. In Phase III, the vaccine is given to thousands of people and tested for efficacy and safety.
Many vaccines undergo Phase IV formal, ongoing studies after the vaccine is approved and licensed. This usually takes place on implementation bases.
Phase 1: In this phase, new interventions/vaccines are tested by Researchers in a small group of people for the first time to evaluate its safety, as well as determine a safe dosage range, and identify side effects.
Phase 2: The intervention is given to a larger group of people to see if it is effective, to further evaluate its safety and eventually to select optimal dosages.
Phase 3: The intervention/vaccine candidate is given to larger numbers of the target group of people to confirm it works (i.e. the efficacy of the intervention), monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
Phase 4: Studies are done after the intervention has been marketed to gather information on the drug’s effectiveness in various populations and any side effects associated with long-term use.
Who were the target age groups for the Malaria Vaccine mosquirix?
The Phase 3 trial of mosquirix enrolled approximately 15,462 infants and young children. There were 2 target age groups: Older children received their first dose of the malaria vaccine between 5 and 17 months of age.
Infants received the vaccine together with other routine childhood vaccines at 6, 10 and 14 weeks of age.
In the face of the evidence base on the phase 3 clinical trials of vaccine in October 2015, the Strategic Advisory Group of Experts (SAGE) on Immunization and the Malaria Policy Advisory Committee (MPAC) jointly convened by WHO to review all evidence regarding RTS,S relevant for global policy. SAGE/MPAC strongly opinion and were not supportive of vaccine use among infants aged 6–12 weeks due to the lower efficacy seen in this age group. However, in the light of this, the SAGE and MPAC recommended that pilot implementation of RTS,S occur in 3–5 settings in sub-Saharan Africa, administering 3 doses of the vaccine to children beginning from 5 months of age and a fourth dose 15–18 months after the third dose. According to SAGE/MPAC, there is a need for large-scale implementation pilots, to evaluate the extent to which the protection demonstrated in children aged 5–17 months in the Phase 3 trial can be replicated in the context of the routine health system, particularly in view of the need for a 4-dose schedule that requires new immunization contacts.
Against this backdrop of 39% efficacy of Mosquirix vaccine, while the vaccine pilots implementation has already been accepted and began, authorities in the various countries, should monitor and assess the extent to which RTS,S or mosquirix vaccination impacts mortality and establish an effective pharmacovigilance centres and surveillance to ascertain adverse effects.
Vaccine effectiveness is a different concept which characterize protection through programmatic implementation, and after a reﬂection on the performance of the vaccine as actually delivered to the target population. Vaccine effectiveness is usually lower than vaccine efﬁcacy as a result of programme-related factors such as errors in vaccine storage, preparation or administration of the vaccine, as well as incomplete coverage. Comparably, the effectiveness of the vaccine can also be greater than expected as a result of the vaccine’s indirect (herd) effects, as has been demonstrated for several vaccines, including pneumococcal and Hib conjugate Vaccines. Therefore, to measure the effectiveness of the current RST,S vaccine, there is a need to monitor the overall impact of the vaccine hence countries may consider appropriate disease surveillance activities following its introduction.
However, as Ghana and other 2 remaining countries have accepted the WHO recommendation hence the vaccine implementation, the following questions perhaps could be ponder on;
Is the disease perceived to be important to the public and the medical community?
Is the vaccine recommended by WHO and is control of this disease in line with
global or Ghana regional priorities?
Does the disease cause signiﬁcant disease burden?
Does preventing the disease contribute signiﬁcantly to the goals and align with the
priorities established in the Ghana national health and development plans (if any)?
Promise Edem Nukunu
The author is a medical Journalist and a member of the Medical Journalists’ Association – Ghana and the World Federation of Science Journalist as well as member of the Global Emerging Pathogens treatment consortium-PLUS faculty.
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