What is the problem/background?

Malaria remains one of the leading causes of infectious disease and deaths worldwide mostly affecting children and pregnant women in sub-Saharan Africa. While globally, the number of new cases of malaria per year decreased between 2010 and 2018, the rate of change slowed from 2014 to 2018. There are several threats to controlling malaria; drug and insecticide resistance, the absence of a licensed vaccine in use and currently the COVID-19 pandemic. Mosquirix™ (RTS, S/AS01E) remains under evaluation in Africa (including studies ongoing in Western Kenya). RTS,S/AS01E is likely to be expensive due to the manufacture process, and even if the current trials in Western Kenya confirm that RTS,S is safe and efficacious when delivered at scale, sustaining funding for ongoing vaccination will be a challenge. R21/Matrix-M (R21/MM) is a candidate malaria vaccine and biologically similar to RTS,S/AS01E. R21/MM vaccine has been found to be safe and well tolerated in children and infants (n=470) when evaluated using 3 vaccinations 4 weeks apart in Burkina Faso (Nanoro-Phase IIb trial, NCT03896724) and Kenya (Kilifi-Phase Ib trial, NCT03580824). The vaccine is manufactured by the Serum Institute of India (SII) and if found to be efficacious will likely be a cost-effective alternative to RTS,S/AS01E given the good immune response seen in these studies. Since R21/MM has been found to be safe, tolerable and elicits good immune responses comparable to the RTS,S/AS01E vaccine, it is important that its efficacy is assessed to provide evidence for further clinical development and licensure with phase III trials in Africa. The option of a second licensed malaria vaccine, likely at lower price than RTS,S/AS01E and higher efficacy, would be beneficial for Kenya.

What question are we trying to answer?

We plan to evaluate if R21/MM, protects infants enrolled at 5-17 months of age from malaria and is safe and well tolerated. Infants will receive a three-dose vaccination course at day 0, 28 and 56 followed by a booster dose at 1 year post the third vaccination and will be followed up at 12 and 24 months following the 3 primary vaccinations.

Where is the study taking place, how many people does it involve and how are they selected?

The study will take place at the KEMRI Centre for Geographic Medicine Research, Coast (KEMRICGMRC). We will recruit approximately 600 healthy infants from the Kilifi population surveillance platform, the Kilifi Health and Demographic Surveillance System (KHDSS), and they should be 5-17 months at enrolment. Approximately 400 of the infants will receive the R21/MM vaccine whilst approximately 200 will receive the control rabies vaccine. Participants will be identified based on their date of birth and locator information available through the KHDSS. The decision on which vaccine they will receive will be based on chance with 2:1 participants receiving the R21/MM vaccine to ensure the results of the study can be reasonably interpreted. We will screen potential participants until we identify the required number of healthy participants. These children will be followed up for 2 years and malaria detected if children present to the KEMRI-CGMRC out-patient facilities at Junju, Pingilikani and Chasimba and the Kilifi County Hospital.

What does the study involve for those who are in it?

Children, whose parents/guardians provide consent and their children pass screening assessments will be enrolled into the study. Blood samples will be taken at up to 7 clinic visits (safety cohort) and additionally 3 finger prick tests to check for evidence of malaria on the days of vaccination in the event of fever or history of fever. Screening will involve a series of blood tests and clinical assessment to check for good health. For individuals who are selected for participation, blood will be drawn at different timepoints as outlined in the schedule of procedures (Table 2) and the amount of blood collected throughout the study will be approximately 30-60 mls depending on the child’s weight and within the limits regarded as appropriate by the World Health Organization (WHO). Repeat blood samples may be taken to verify abnormal results or if clinically indicated. Medical history will also be obtained and a clinical assessment performed to exclude any major health conditions. Those that pass screening will be enrolled in the trial and if a clinically significant condition is identified participants will be counselled as appropriate then referred to a government facility for further management. Once the participants are successfully screened, they will be invited for the first vaccination (Day 0). Following vaccination, participants will be observed for at least 30 minutes to check for any reactions. There will be a total of 10 clinic visits; 6 clinic visits, 4 vaccinations visits and up to 10 telephone calls to document any medical events post vaccination. In the 6 days following vaccination information will be gathered on any side effects to vaccination either over the phone or in person. The three vaccinations will occur on day 0, 28 and 56 and a booster vaccination one year after the third vaccination. The study duration for each participant will be 2 years.

What are the benefits and risks/costs of the study for those involved?

Studies in Kenya and Burkina Faso have shown that the vaccine is safe, tolerable and elicits good immune responses in children and infants. Participants may benefit from receipt of the vaccine given the promising efficacy data (up to 77% protected from disease) seen from the previous trial in 450 children in Burkina Faso. It remains to be demonstrated in large scale trials if the vaccine effectively prevents malarial disease and its complications. Participants will also have close oversight and treatment support from the study team although this will primarily be for risk monitoring. There will also be wider benefit in the field of malaria vaccine research in building on data available on safety, efficacy and immune responses to R21/MM which will help with the WHO’s aim to identify a malaria vaccine with high protection rates. Although the administration schedule of the rabies vaccine being used has been evaluated in clinical trials it is currently not standard practice, therefore for all children we will recommend that should they have exposure to high risk bite during the trial they get full post-exposure prophylaxis. There are also minor risks of bruising and infection associated with venepuncture and vaccination but these are minimised by appropriate training of study staff and use of sterile equipment. Participants will not bear any costs as a result of participation in this trial. Participants will also be compensated for transport costs based on distance travelled according to rates for public transport and compensated for out of pocket expenses (350 KSH). These costs will vary but may be up to approximately 2000/- per visit when catering for refreshments and additional transport requirements (spouse, siblings, impartial witness etc.).

In 2018, there were an estimated 228 million malaria cases worldwide, resulting in 405, 000 deaths. 93% of these occurred in the WHO African Region. In this region, Plasmodium falciparum is the most prevalent malaria parasite causing 99.7% of the estimated malaria cases. In the era of emerging possible parasite resistance to artemisinin-based drugs and wide-spread resistance among malaria vectors to insecticide classes used to treat bed nets or for indoor residual house-spraying, there is an urgent need for a highly efficacious vaccine to combat the stalling reductions in the malaria burden in Africa. Currently, RTS,S/AS01E is the most advanced malaria vaccine. However, the vaccine demonstrated moderate efficacy against clinical malaria in infants (28.3%; 95% CI 23.3-32.9) aged 6-12 weeks who received 3 vaccinations 4 weeks apart with or without a booster vaccination at 20 months. Implementation of the vaccine is currently under evaluation in Kenya, Malawi and Ghana to establish safety when distributed at scale and impact on mortality. Vaccines against malaria offer real hope for the continent, as resistance and difficulties in sustaining a complete coverage of vector control continue to pose major challenges. While RTS,S/AS01E offers some early hope, this is the only registered malaria vaccine and it is expensive. The estimated cost of RTS,S/AS01E at 7$ per dose will also be substantial if a 3-dose regime and booster(s) are considered in the KEPI schedule. The provision of an alternative, safe and efficacious vaccine candidate would increase Kenya’s options and notably related to the sustainable cost implications. One option in the development pipeline is R21/MM. Preliminary data suggest R21/MM is safe, immunogenic and prevents disease in African infants. R21 was designed to have a higher ratio of malaria antigen (i.e. circumsporozoite protein (CS)) to hepatitis B surface antigen. This allows immunogenicity to be sustained with lower doses than with RTS,S/AS01E, but does not translate into higher levels of immunogenicity than RTS,S/AS01E when judged by antibody concentrations. However, it appears that the antibody is of improved quality, since protective efficacy in both mouse and human challenge studies is higher than that observed with RTS, S/AS01E. Furthermore, the manufacture process for R21 is improved and likely to be less costly than RTS,S/AS01E. Overall, R21/MM has been shown to be safe and well tolerated across the UK and Africa (Kenya and Burkina Faso) in phase I and II trials. We will conduct a phase III randomized control trial to evaluate the efficacy of R21/MM vaccine in children (aged 5-17 months at enrolment) against clinical malaria. This is a multicentre trial with sites in Bougouni; Mali, Nanoro; Burkina Faso, Dande; Burkina Faso, Bagamoyo; Tanzania as well as Kilifi; Kenya. Each participant will be screened to ensure they are in good health based on clinical assessment and laboratory results. Each participant will have 10 clinic visits and additional safety assessments in the week following vaccination for the safety cohort. Of approximately 600 participants to be enrolled in Kilifi, 50% will be randomised to the safety cohort. Participants will receive three vaccinations at day 0, 28, and 56 and a booster dose at 12 months post third vaccination. For the safety cohort; 1) Following each vaccination, participants will be assessed for solicited and unsolicited adverse events either at home or on the phone, 2) Blood will be taken during the clinic visits for safety and/or immunological analysis.