Developing capacity for implementation and evaluation of vaccine trials in Uganda: Perspective of the Makerere University Walter Reed Project

Introduction Infectious diseases and neglected tropical diseases continue to be a major challenge in resource limited settings, causing significant morbidity and mortality. Although vaccines are a key biomedical prevention tool, resource limited settings often lack the infrastructure, regulatory frameworks, and skilled human resource to conduct vaccine clinical trials. To address this gap, the Makerere University Walter Reed Project (MUWRP) was established and has contributed to vaccine research in Uganda and globally. Methods This was achieved through training a strong vaccine clinical trial workforce; development of requisite clinical trial infrastructure for research activities and management of investigational products; conducting phase I-III vaccine trials and contribution to national ethical and regulatory frameworks that protect participants. Results As of 2022, MUWRP had successfully conducted and completed five phase I/II HIV vaccine clinical trials, five for Ebola and Marburg, while one phase I/II Schistosomiasis and one phase III COVTD-19 vaccine clinical trial are ongoing. Discussion The completed vaccine trials provided critical scientific knowledge on the safety and immunogenicity of investigational products which informed the design of better vaccines for diseases of global health importance. Conclusion Academia, through establishment of appropriate partnerships can contribute to the identification of solutions to complex public health challenges.


Introduction
The development of safe and effective vaccines has been vaccines to 25 infectious diseases 1 . However, there is an urgent need to develop vaccines for prevalent, endemic pandemic further underscored the relevance of vaccine development for the prevention of infectious diseases of public health concern 2 . That said, there is a paucity of information on developing capability for vaccine research in sub-Saharan Africa 3 . - [4][5][6] . Although numerous pub-

Methods
About MUWRP tion, whose mission is to mitigate disease threats through quality research, health care and disease surveillance. The project's scope includes clinical research; the Presidential -veillance, one health and global health security; and the pability program whose primary objective is to establish a strong clinical trial workforce; developed critical infrastructure for research activities, data management, information technology, laboratory testing and storage; aligned research awareness, buy in and political will; and instituted ethical and regulatory frameworks that protect participants. Hereunder we describe how these capabilities were achieved.

Human Resource Development
standards in order to generate credible data that informs prioritization of biological products 11 . To achieve this, MUWRP developed a diverse workforce including physinurses, laboratory scientists, clinical research coordinapharmacists, quality and compliance specialists, data management staff, and grants managers for clinical trial implementation. Training included general clinical trial training, Good Clinical Practice (GCP), Good Clinical Laboratory Practice (GCLP), Human Subjects' Protection (HSP), standard of International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) 12 . Regular competence assessments to ensure maintenance of these skills are conducted throughout the period of employment. Collectively the staff have re-Establishing VCT Infrastructure MUWRP's infrastructure development was guided by ICH and international partners. Initial space allocation at commodate the research clinic, laboratory and adminis-search clinic has 12 well-equipped clinic rooms for private physical examination and counselling, a well-equipped phlebotomy room, a waiting area, plus secure records and 13 . A research pharmacy equipped with a biosafety level II (BSL-2) 0 C and -40 0 C) and 2 refrigerators monitored by digital thermometers with temperature and humidity data loggers was established. It manages investigational products according to national and international pharmacy is restricted by key and biometrics.

Data Management and IT Infrastructure
Integrity, safety, and validity of trial data is critical to the evaluation of vaccines. MUWRP instituted a data manand process vaccine trial data according to Health Insur-ance Portability and Accountability Act (HIPAA) privacy -ized Enterprise grade core servers and clusters. A secure relational databases and synchronously replicates data backups across redundant secondary sites was also developed. Investments in a defense in-depth approach which secures all mobile devices, workstations and servers through endpoint signature-based security, web proxcontrol by training data entry and management specialists; acquiring analytical infrastructure and software (e.g., the Clinic Appointment Scheduling & Tracking (CAST) system which tracks attendance, scheduling and follow-up for vaccine trial participants.

Laboratory Capacity
Laboratory capacity for moderate and highly complex testing is a challenge in resource limited settings 14-16 . MU-WRP established its clinical and research BSL-2 laboratory at the MakCHS and immediately instituted processes leading to College of American Pathologists' accreditation in 2005. This accreditation has been maintained through a rigorous continuous quality assurance and quality improvement program, based on GCLP 17 . The laboratory has capacity for safety tests, light microscopy, diagnostic immunology, cellular immunology, molecular diagnostics, and biological specimen processing and cryopreservation. A robust laboratory information management syso C and liquid nitrogen freezers supported by 2 liquid nitrogen plants lished. There is in-house capacity for shipping specimens for complex testing following International Air Transport Association standards. All laboratory work is handled by scientists and technologists.

Financial Management Capability
nancial capability of institutions to manage grants and procure supplies. MUWRP invested in a robust accounting system that supports budgeting, expenditure tracking, forecasting and reporting per funder requirements. MU-WRP further adheres to Generally Accepted Accounting Principles and cost principles of (U.S.) federal contracting that meet the standards of the Comptroller General of the U.S Government, and is regularly audited by internal and external auditors. Relatedly, MUWRP developed a supply chain management system that adheres to internationally acceptable procurement principles and practices in accordance with the Federal Acquisitions Regulations of the U.S.

Community engagement
participation of communities most affected by the disease in question . Community engagement entails research education, efforts to allay fears and correct myths and misconceptions, and winning community trust to create partnerships in vaccine development [20][21][22] . MUwhere members of the community, policy makers and researchers work together to address health-related issues. MUWRP further formed a community advisory board with representation from former trial participants, religious leaders, the media, politicians, civil society, and key and vulnerable populations, who meet regularly to review are relevant to the population and community voices are heard. Policy makers and politicians are engaged on the importance of vaccine research in the country (Picture 1). When a clinical trial requires participation of vulnerable populations, peer leaders support recruitment and retention. Table 1 highlights some of the community engagement challenges and their solutions. Access to key populations such as commercial sex workers Use of sub-advisory boards that are populationfocused; an improvement from the snowballing mechanisms of identifying potential participants Participant expectations for healthcare beyond the provisions and lifetime of the trial Continuous participant education on the trial requirements, provisions and limitations

Instituting an Ethical and Regulatory Framework for VCTs
and Africa raised many questions concerning the availability of an ethical and regulatory framework for equity in biomedical research in Uganda 4, 10, 23, 24 . MUWRP set up a regulatory, quality and compliance department to ensure trial compliance with local (Research Ethics Committees, Uganda National Council for Science and Techetc.) guidelines for research involving human subjects. This department scrutinizes protocols prior to submission for review to national regulatory authorities, tracks and follows up all regulatory correspondence, internally monitors trials, reports adverse events and deviations, organizes continual staff trainings, submits annual progress reports, obtains subsequent trial approvals in a timely manner, and maintains all pertinent documentation. All these processes are guided by a quality management plan Training on laboratory research and quality systems MUWRP offers internships to students and graduates from Makerere and other universities on laboratory processes, GCLP, biosafety, among others. Students are actively supported to utilize the laboratory infrastructure

Picture 1: Dr. Kibuuka (Executive Director) addressing parliamentarians about HIV vaccine research
for postgraduate research, including basic sciences projects. In addition, the laboratory conducts didactic and hands-on training on GCLP for other clinical research sites (CRS) and private health facilities in Uganda.

Results
In light of the above processes, MUWRP has grown into master of science and 3 doctor of philosophy students, and has supported the improvement of quality management systems in two regional referral hospitals (Fort Portal and Kayunga), leading to laboratory accreditation 25 . In addition, MUWRP has successfully conducted 12 Phase has conducted and their key outcomes.

RV 156, 2004
uated the safety and immunogenicity of a multiclade well-tolerated and this trial laid the foundation for design

RV 172, 2006
--ed adults in East Africa. The vaccine was safe and well 63% of vaccinees, with titers of preexisting Adenovirus serotype 5 (Ad5) neutralizing antibody not affecting the frequency and magnitude of T cell responses in primeboost recipients 26 . The vaccines were further tested in unique subpopulations in a phase 2b trial in the US to 27 .

RV 247, 2009
-Ebola or Marburg vaccine clinical trial in Africa, and the results showed that, given separately or together, both vaccines were well tolerated and elicited antigen-specific humoral and cellular immune responses, thus contributing to expedited development of more potent Ebola virus vaccines that use the same wild-type glycoprotein antigens .

RV 262, 2012
GAG) administered by intramuscular Biojector® 2000 or Cellectra® intramuscular electroporation device fol--Results showed that cellular responses were observed in inant, including high rates of binding antibody responses to CRF01_AE antigens. Electroporation did not confer prime for this regimen . Discussion tious diseases. The current efforts to reach herd immuresearch in addressing national and global public health threats. There is need for stronger vaccine trial capability in resource limited settings for effective response to emerging and re-emerging infectious disease threats. This article has highlighted MUWRP's progress towards setdiscusses below, the impact of these initiatives towards national and global efforts in prevention of infectious diseases.

Impact in Uganda and globally
Although the majority of vaccine clinical trials presented are early phase trials, the knowledge attained has contrib-vectored vaccines that were tested during the 2014-2016 Ebola virus disease outbreak in West Africa 32 . The EBtested at two CRS in Uganda (including MUWRP) 31 were approved by the European Union for prophylactic use during Ebola outbreaks. In addition, safety and immunohave contributed to the body of knowledge guiding the design of investigational products for the prevention 26 and treatment 33 critical need for new preventive interventions.

Contribution to Building Capacity of other Vaccine Research Institutions in Uganda
MUWRP has contributed to the critical mass of clinical, laboratory and sociological researchers in the country. Many staff who trained and worked at MUWRP have moved on to successfully set-up or support other CRSs, establishing a foundation for locally designed research protocols. Staff actively contributed to the development of the National Guidelines for Research involving Humans as Research Participants, the Uganda National Health Laboratory Services policy and the national biosafety and biosecurity guidelines and regulations. MUthrough presentations at national and international sciengenerated from vaccine clinical trials. In addition, staff are members of key Ministry of Health technical working groups that de-ments within and outside Makerere University have resulted in collaborations with both local and international colleges, universities, pharmaceutical and research bodies that have created new training and research opportunities for scientists in Uganda. MUWRP's state-of-the-art infrastructure continues to build national capacity and capability for the conduct of complex vaccine trials through training, mentorship and internships.

Conclusion
cation of vaccine products for the prevention of diseases, but the lack of adequate infrastructure, skilled personnel and effective ethical and regulatory frameworks may limit their conduct in low resource settings. This article summarizes the efforts and results of building local capacity and capabilities for the successful conduct of impactful strates how partnerships between academia (MAKCHS) and non-academic organizations can develop skills, infrastructure and frameworks for the evaluation of appropriate solutions to infectious disease threats.