Safety assessment of malaria vaccines in african populations: exemplified by the assessment of PfSPZ based vaccines in Tanzania and equatorial Guinea

Malaria is a major global health problem, with persistent public health challenges especially in sub-Saharan Africa. An upswing in malaria clinical cases is reported by the WHO from 214,200,000 in 2015 to 219,000,000 in 2017. The latest WHO’s World malaria report, has estimated 627,000 malaria deaths worldwide in 2020 representing about 69,000 more deaths in 2020 compared to 2019 (WHO, 2021). Although, disruptions in the provision of malaria prevention, diagnosis and treatment during the Covic-19 pandemic were linked with approximately two thirds of these additional deaths, evidence exists which suggest an existing real threat to the effectiveness of insecticide-based vector control and antimalarial drugs due to developing resistance towards these tools (Namias et al., 2021; Vaulin et al., 2019). Apparently, if the goal of malaria elimination is to be achieved interventions that can prevent infection and thereby block transmission are needed. Integration of malaria interventions with immunization, complements Global Immunization Vision and Strategy (GIVS), an agenda created by the WHO and UNICEF (Lindstrand et al., 2021; WHO, 2020). The WHO rainbow tables outline several malaria vaccine candidates at different clinical development stages including; Pre-erythrocytic stage projects (eg. RTS,S-A01, PfSPZ Vaccine etc), blood stage projects (eg. P27A Vaccine etc), other projects (eg. PfSPZ-CVac (PfSPZ Challenge + chloroquine)) most of which have been or are being tested across different countries including malaria endemic regions in Africa. Complexities of conducting field trials have been the center of discussion since the early periods of searching for malaria vaccine on proper safety assessment involving areas where the prevalence, importance and epidemiology of malaria is known (Liheluka et al., 2013; McGregor, 1979; Powell, 1979). Over years, research institutions in Africa have developed capacity and are now able to conduct good clinical (GCP) and laboratory practices (GLP) compliant clinical trials and such interest is growing. This important milestone will help to accelerate clinical development programs of several vaccine candidates and other investigational products of public health importance in endemic countries. As a matter to assess, build and strengthen the capacity of different sites to implement these trials, early trials were designed to reproduce the results obtained in Europe and America with minor modification of protocols and standard operating procedures (SOPs) to fit the situation. The need to achieve optimal safety assessment, proper interpretation and reporting, for local investigators, cannot be overstated. The broader concept of safety assessment must be understood as, the process beyond mere assessment of findings from the individual parameters following exposure to IMP, but rather as, the process of safety assessment that is adequate for; relevant participant selection, safe administration of IMP, proper safety follow-up, compliance to safety reporting to local regulatory authorities and relevant final clinical safety report. Interpretation of safety findings in reference to the socio-cultural and baseline epidemiological and clinical characteristics of the local population being assessed has potential to provide fundamental bridge between the intervention being assessed and the local healthcare system, enabling proper use of resources as well as the relevant and timely key policy decisions to be made. Known epidemiological characterization among different African populations may provide an indication that, these communities are similar and with further exploration, procedures may be optimized and synchronized at a level that allows operational shift from the so called African sites to African research centers.
Methods and findings
In the first part of this thesis (Chapter 4), the aim was to generate the safety and tolerability profiles of PfSPZ based malaria vaccine candidates namely PfSPZ Vaccine and PfSPZ-cVac in malaria endemic African population, targeting to develop and implement a vaccine that can be used as additional tool for malaria intervention and possibly elimination, that is well tolerated and safe. As a toolkit for malaria control in Africa, the PfSPZ vaccines are designed to prevent infection. We worked on assessing safety of PfSPZ vaccine candidates by conducting a series of randomized, placebo-controlled, double-blind clinical trials in two African countries (Tanzania and Equatorial Guinea) through the program built on strong South-South / North-South collaboration platform. We designed and conducted the clinical trial protocols covering spectrum of age groups ranging from adults (with and without HIV infection) to the target pediatric population of healthy adolescents, children and infants. The clinical development plan that we pursued focused on addressing safety concerns related to PfSPZ vaccines, including; (i) feasibility of administration via direct venous inoculation (DVI) across age groups; (ii) possibility of breakthrough malaria infections due to inadequate attenuation; (iii) possibility of significant local side effects at the injection site that sporozoites may contribute; (iv) possibility of significant systemic reactogenicity caused by PfSPZ Vaccine; (v) possibility of effects on the rates of AEs related to geographical locations among African population, age or dose; (vi) possibility of significant increase in AEs with repeated dosing; (vii) possibility that the accelerated vaccination schedule regimens of PfSPZ Vaccine are significantly intolerable. Through this work, we performed; The first demonstration of PfSPZ Vaccine efficacy against PfSPZ Challenge in healthy adults population (PAPER I); the first demonstration of safety and tolerability of PfSPZ Vaccine in infants and children along with demonstration of the safety and exploration of efficacy of Sanaria’s PfSPZ vaccine using PfSPZ-CHMI in African adults (Paper II and Paper III); the demonstration of safety and tolerability of Sanaria’s chemo-attenuated vaccine (PfSPZ-CVac) in Equatorial Guinea (Paper IV); the first demonstration of safety and tolerability of PfSPZ Vaccine and exploration of efficacy of Sanaria’s PfSPZ vaccine using PfSPZ-CHMI in individuals living with HIV (Paper V); the demonstration of safety and tolerability of accelerated vaccination regimens of PfSPZ Vaccine and down-selection of optimal regimen for pivotal trials in Africa (Paper VI). A meta-analysis of AE data for adults and children using forest plots of total solicited AEs in vaccinees and placebos in the randomized, double-blind, placebo-controlled trials analyzed to date has shown in all cases, 95% confidence intervals cross a ratio of 1, indicating no differences between vaccinees and controls.
In the second part of this thesis (Chapter 5), the aim was to optimize recruitment and enrolment process through better understanding of the social-cultural, epidemiological and clinical characteristics of the local population. Due to factors ranging from social-cultural to the local clinical research implementation and regulation systems, synchronization of recruitment and enrolment strategies with the local population characteristics, will potentially contribute to the successful clinical development plan for interventions. Fundamental to such success are the components such as, proper use of resources, better alignment; to the daily social-cultural activities and the local healthcare systems, timely recruitment, preparation of the risk mitigation plans relevant to the communities being assessed, reliable interpretation of safety results and precision in estimating risk benefit ratio of the intervention to the local community. In these regards, we designed and conducted pilot epidemiological assessments within study areas located in eastern and western parts of Africa, (Bagamoyo, Tanzania) and (Bioko Island, Equatorial Guinea) respectively. The pilot assessments were implemented through separate protocols linked to the processes in main trial protocols on community engagement and sensitization to ensure that, all members of the target population including infants and children, plus HIV positive individuals are able to participate in GCP compliant clinical research in Africa. Through these activities, we formulated a simple and yet very effective categorization of recruitment and screening criteria across the protocols being; (1) criteria assessing GCP compliance; (2) criteria assessing protocol compliance; (3) clinical criteria assessing health status and (4) laboratory criteria assessing health status. By applying this seemingly simple categorization of criteria we piloted relevant allocation of limited resources between community-based and clinic-based recruitment and screening processes. Over 6,000 people were screened with subsequent registration of potential participants for future clinical trials (Paper VII).
In the third part of this thesis (Chapter 6), the aim was to optimize the processes for safety assessment, interpretation and reporting of results through the application of locally relevant toxicity grading tools in reference to the standard toxicity grading systems adopted to the local clinical and laboratory population parameters. Reporting requirements to the local regulatory authorities’ entail expedited reporting for certain AE grades following IP administration. It is critical that, sponsors and investigators adhere to such requirements for compliance and that the local use of standard toxicity grading systems recommended by the US-FDA, CTCAE and other relevant systems must be properly adopted and hence, optimized to enable proper clinical care for participants and to avoid over- or under-reporting of important safety observations. US-FDA recommends for the local reference values to be considered when the parameter limit values are defined in the guidance or some cases may even require the exercise of clinical judgment. The main reason for this is, such reference systems were developed primarily using data collected from certain population, and therefore are only practically relevant if directly used to the population with similar characteristics. Even for population from the same geographical locations, ethnic differences may require proper adjustments to be made. To achieve this optimization, we applied the methodology stipulated by the CLSI for analysis of reference intervals based on local clinical and laboratory data to and developed a listing of clinical and laboratory reference intervals applicable for local populations which were then integrated to the known standard toxicity grading systems (USFDA, CTCAE ect) to develop locally relevant toxicity grading scales. Site based, QA-controlled manual of reference intervals and toxicity grading was developed for the local population and has since been used for standardized interpretation and reporting of results during safety assessments at screening, enrolment and follow-up.
Conclusion
Evaluation of potential relevant health interventions tailored to collaborations involving South-South / North-South partnerships linking multiple sites in Africa, is the peculiar platform to demonstrate and promote the potential reproducibility of processes and results, with reasonable justification for their application across sites. Through such a platform, standardizations that we made on the optimization-approaches for enrolment practices and for interpretation of results and assessment of abnormal clinical and laboratory parameters, played essential role enabling reproducibility of procedures across sites. Fundamental to the benefit of such standardizations, is the potentially reasonable justification for application of results from evaluations across sites. In the scope of this thesis, the assessments that we performed, provided results indicating that, the safety profile of malaria vaccine candidates is determined by the product itself rather than the type of African population in which it is tested. Strategic partnerships created an enabling platform for interactions with multiple regulatory authorities, ethical committees and IRBs, a critical component reflecting independent reviews for the protocols and reporting of results. With the spectrum of available malaria vaccine candidates including the PfSPZ based, these findings will enable accelerations of clinical development plans not only for clinical trials accessing malaria vaccines but all other related interventions. Our perspective is to maintain the portfolio of activities and skill base that will streamline implementation for subsequent programs of work. In addition, this work has spearheaded the establishment of the clinical research capacity for conduct of regulatory trials in Equatorial Guinea, with primary support from the Bagamoyo Clinical Trials Facility investigators from Tanzania, and used the clinical trials platform to support several masters and PhD training of colleagues in Tanzania, Equatorial Guinea and from partner institution’s outside Africa. This work is built on the strong South-South and North-South collaborations enabling and strengthening synchronization of procedures among clinical trials conducted in different African communities at a level that will allow operational shift from the so called African research sites to African research centers.