The promise, problems, and pitfalls of including pregnant women in clinical trials of Lassa fever vaccine: a qualitative assessment of sub-Sahara Africa investigators' perception.

Introduction: Lassa fever runs a uniquely severe course in pregnancy. There are plans for Lassa fever vaccine clinical trials in endemic West African countries. We assessed the perception of West African investigators to include pregnant women in these studies. Methods: interviews were conducted with eight sub-Saharan African investigators. These investigators, listed as speakers at the 9th European and developing countries clinical trials partnership (EDCTP) congress and had clinical research experience in sub-Saharan Africa, were purposefully included as study participants. Six are from West Africa. The information was analyzed thematically. Results: we interviewed eight (six in-person and two on the phone) out of fifteen earmarked investigators. Respondents had limited experience with pregnant women in clinical trials, but desired a paradigm shift. They identified pregnant women's willingness, a robust community engagement strategy, and adequate safety data as enablers, while lack of safety data, persistent fears about potential harm to pregnant women and offspring, and inappropriate community engagement activities as potential barriers. Conclusion: the inclusion of pregnant women in Lassa fever vaccine clinical trials should be a priority of vaccine developers. Investigators are willing to conduct these studies provided adequate measures to ensure safety is in place.

A systematic scorecard-based approach to site assessment in preparation for Lassa fever vaccine clinical trials in affected countries.

BACKGROUND: We sought to develop and test an objective scorecard-based system for assessing and categorizing available research sites in Lassa fever-affected countries based on their preparedness and capability to host Lassa fever vaccine clinical trials. METHODS: We mapped available clinical research sites through interrogation of online clinical trial registries and relevant disease-based consortia. A structured online questionnaire was used to assess the capability of clinical trial sites to conduct Lassa fever vaccine clinical trials. We developed a new scoring template by allocating scores to questionnaire parameters based on perceived importance to the conduct of clinical trials as described in the WHO/TDR Global Competency Framework for Clinical Research. Cutoff points of 75% and 50% were used to categorize sites into categories A, B, or C. RESULTS: This study identified 44 clinical trial sites in 8 Lassa fever-affected countries. Out of these, 35 sites were characterized based on their capacity to hold Lassa fever vaccine clinical trials. A total of 14 sites in 4 countries were identified as ready to host Lassa fever vaccine trials immediately or with little support. CONCLUSION: It is feasible to hold Lassa fever vaccine trials in affected countries based on the outcome of the survey. However, the findings are to be validated through sites' visits. This experience with a standardized and objective method of the site assessment is encouraging, and the site selection method used can serve as an orientation to sponsors and researchers planning clinical trials in the region.

Correction: Phase I Clinical Trial of a Recombinant Blood Stage Vaccine Candidate for Plasmodium falciparum Malaria Based on MSP1 and EBA175.

[This corrects the article DOI: 10.1371/journal.pone.0117820.].

Phase I Clinical Trial of a Recombinant Blood Stage Vaccine Candidate for Plasmodium falciparum Malaria Based on MSP1 and EBA175.

BACKGROUND: A phase I randomised, controlled, single blind, dose escalation trial was conducted to evaluate safety and immunogenicity of JAIVAC-1, a recombinant blood stage vaccine candidate against Plasmodium falciparum malaria, composed of a physical mixture of two recombinant proteins, PfMSP-1(19), the 19 kD conserved, C-terminal region of PfMSP-1 and PfF2 the receptor-binding F2 domain of EBA175. METHOD: Healthy malaria naïve Indian male subjects aged 18-45 years were recruited from the volunteer database of study site. Fifteen subjects in each cohort, randomised in a ratio of 2:1 and meeting the protocol specific eligibility criteria, were vaccinated either with three doses (10 µg, 25 µg and 50 µg of each antigen) of JAIVAC-1 formulated with adjuvant Montanide ISA 720 or with standard dosage of Hepatitis B vaccine. Each subject received the assigned vaccine in the deltoid muscle of the upper arms on Day 0, Day 28 and Day 180. RESULTS: JAIVAC-1 was well tolerated and no serious adverse event was observed. All JAIVAC-1 subjects sero-converted for PfF2 but elicited poor immune response to PfMSP-1(19). Dose-response relationship was observed between vaccine dose of PfF2 and antibody response. The antibodies against PfF2 were predominantly of IgG1 and IgG3 isotype. Sera from JAIVAC-1 subjects reacted with late schizonts in a punctate pattern in immunofluorescence assays. Purified IgG from JAIVAC-1 sera displayed significant growth inhibitory activity against Plasmodium falciparum CAMP strain. CONCLUSION: Antigen PfF2 should be retained as a component of a recombinant malaria vaccine but PfMSP-1(19) construct needs to be optimised to improve its immunogenicity. TRIAL REGISTRATION: Clinical Trial Registry, India CTRI/2010/091/000301.

Roadmap for the establishment of a European vaccine R&D infrastructure.

To consolidate the integration of the fragmented European vaccine development landscape, TRANSVAC - the European Network of Vaccine Research and Development, funded by the European Commission (EC) - has initiated the development of a roadmap through a process of stakeholder consultation. The outcome of this consultation highlighted the need for transnational cooperation and the opportunities that could be generated by such efforts. This cooperation can be achieved through the establishment of a European Vaccine Research and Development Infrastructure (EVRI). EVRI will support cooperation between existing vaccine Research and Development (R&D) organisations from the public and private sector and other networks throughout Europe. It will become sustainable over time by receiving support from multiple sources including the EC, European Union (EU) Member States, European vaccine companies, EVRI partner organisations, and by income generated. Different stakeholders have demonstrated support for the concept of a vaccine infrastructure and agree that such an infrastructure can function as leverage institution between public and private institutions thus making significant contributions to the vaccine field as a whole in its quest to develop vaccines. EVRI will be launched in three phases: preparatory (during which the legal and administrative framework will be defined and a business plan will be elaborated), implementation and operational. If sufficient political and financial commitment can be secured from relevant national and European entities as well as from the private sector and other stakeholders, it could enter into operational phase from 2017 onwards. In conclusion, EVRI can make vaccine R&D more efficient and help address European and global health challenges, help alleviate the burden and spread of infectious diseases, thus contributing to the sustainability of public healthcare systems.

European Vaccine Initiative: lessons from developing malaria vaccines.

For over 10 years, the European Vaccine Initiative (EVI; European Malaria Vaccine Initiative until 2009) has contributed to the development of 24 malaria candidate vaccine antigens with 13 vaccine candidates being advanced into Phase I clinical trials, two of which have been transitioned for further clinical development in sub-Saharan Africa. Since its inception the EVI organization has operated as a funding agency, but with a clear service-oriented strategy. The scientific successes and difficulties encountered during these years and how these efforts have led to standardization and harmonization in vaccine development through large-scale European consortia are discussed. In the future, the EVI will remain instrumental in the pharmaceutical and clinical development of vaccines against 'diseases of poverty' with a continued focus on malaria. EVI will continue to focus on funding and managing preclinical evaluation up to Phase I/II clinical trials and strengthening the vaccine-development infrastructure in Europe, albeit with a global orientation.

A randomized controlled phase Ib trial of the malaria vaccine candidate GMZ2 in African children.

BACKGROUND: GMZ2 is a fusion protein of Plasmodium falciparum merozoite surface protein 3 (MSP3) and glutamate rich protein (GLURP) that mediates an immune response against the blood stage of the parasite. Two previous phase I clinical trials, one in naïve European adults and one in malaria-exposed Gabonese adults showed that GMZ2 was well tolerated and immunogenic. Here, we present data on safety and immunogenicity of GMZ2 in one to five year old Gabonese children, a target population for future malaria vaccine efficacy trials. METHODOLOGY/PRINCIPAL FINDINGS: Thirty children one to five years of age were randomized to receive three doses of either 30 µg or 100 µg of GMZ2, or rabies vaccine. GMZ2, adjuvanted in aluminum hydroxide, was administered on Days 0, 28 and 56. All participants received a full course of their respective vaccination and were followed up for one year. Both 30 µg and 100 µg GMZ2 vaccine doses were well tolerated and induced antibodies and memory B-cells against GMZ2 as well as its antigenic constituents MSP3 and GLURP. After three doses of vaccine, the geometric mean concentration of antibodies to GMZ2 was 19-fold (95%CI: 11,34) higher in the 30 µg GMZ2 group than in the rabies vaccine controls, and 16-fold (7,36) higher in the 100 µg GMZ2 group than the rabies group. Geometric mean concentration of antibodies to MSP3 was 2.7-fold (1.6,4.6) higher in the 30 µg group than in the rabies group and 3.8-fold (1.5,9.6) higher in the 100 µg group. Memory B-cells against GMZ2 developed in both GMZ2 vaccinated groups. CONCLUSIONS/SIGNIFICANCE: Both 30 µg as well as 100 µg intramuscular GMZ2 are immunogenic, well tolerated, and safe in young, malaria-exposed Gabonese children. This result confirms previous findings in naïve and malaria-exposed adults and supports further clinical development of GMZ2. TRIAL REGISTRATION: ClinicalTrials.gov NCT00703066.

Safety and immunogenicity of the malaria vaccine candidate GMZ2 in malaria-exposed, adult individuals from Lambaréné, Gabon.

Malaria is still one of the major public health threats in sub-Saharan Africa. An effective vaccine could be a sustainable control measure that can be integrated into existing health infrastructures. The malaria vaccine candidate GMZ2 is a recombinant fusion protein of conserved parts of Plasmodium falciparum Glutamate Rich Protein and Merozoite Surface Protein 3 adjuvanted with aluminium hydroxide. GMZ2 is immunogenic and well tolerated in malaria-naive adults from Germany. To assess safety and immunogenicity in malaria-exposed individuals, 40 adults from Lambaréné, Gabon were randomly assigned to receive either 100 µg GMZ2 or a rabies control vaccine three times in monthly intervals. Both vaccines were well tolerated. One month after a full course of vaccination, GMZ2-vaccinated individuals had 1.4-fold (95% confidence interval: [1.1, 1.7]) higher baseline-corrected anti-GMZ2 antibody levels and more GMZ2-specific memory B-cells compared to the rabies group (p=0.039), despite a high prevalence of GMZ2-specific immune reactivity due to previous intense exposure to P. falciparum.

European Malaria Vaccine Initiative: portfolio and perspectives for the future.

Over the past ten years, EMVI has continually strived to maintain its main goal of accelerating the development of candidate malaria vaccines by facilitating the translational gap between promising experimental malaria vaccines and subsequent clinical trials in Europe and in Africa. To date, EMVI has funded approximately ten vaccine formulations (antigen-adjuvant combination) by developing GMP materials and sponsoring subsequent human clinical trials. In recent years EMVI's role has expanded into harmonization activities relevant to malaria vaccine development as well as making contributions to global coordination efforts in the field of malaria vaccine research and development (R&D). In the next five years, EMVI will be coordinating the European Network of Vaccine Research and Development, an European Commission supported action implementing a vaccine development infrastructure for Europe. By stimulating collaboration, cooperation, networking and joint integrated activities across various fields of research and diseases, and by facilitating the federation of research infrastructures, EMVI is acting today as a catalyst for tomorrow's vaccines.

Safety and immunogenicity of GMZ2 - a MSP3-GLURP fusion protein malaria vaccine candidate.

Malaria is a major public health problem in Sub-Saharan Africa. In highly endemic regions infants, children and pregnant women are mostly affected. An effective malaria vaccine would complement existing malaria control strategies because it can be integrated in existing immunization programs easily. Here we present the results of the first phase Ia clinical trial of GMZ2 adjuvanted in aluminium hydroxide. GMZ2 is a malaria vaccine candidate, designed upon the rationale to induce immune responses against asexual blood stages of Plasmodium falciparum similar to those encountered in semi-immune individuals. Ten, 30 and 100 microg of GMZ2 were well tolerated in 30 healthy malaria-naïve German volunteers when given three times in monthly intervals. Antigen-specific antibodies as well as memory B-cells were induced and detectable throughout the one year follow-up of the study. We conclude that GMZ2 is a safe and immunogenic malaria vaccine candidate suitable for further clinical development.

Safety, immunogenicity, and antibody persistence of a new meningococcal group A conjugate vaccine in healthy Indian adults.

We performed a double-blind, randomized, controlled phase I study to assess safety, immunogenicity, and antibody persistence of the new meningococcal group A conjugate vaccine (PsA-TT) in healthy volunteers aged 18-35 years. Of the 74 male subjects enrolled, 24 received the PsA-TT vaccine (Group 1), 25 received the Meningococcal Polysaccharide Vaccine A+C, Pasteur, Lyon, France (Group 2), and 25 received the Tetanus Toxoid Vaccine Adsorbed, SIIL, Pune India (Group 3). No immediate reactions were observed. Local and systemic solicited reactions within 7 days post-vaccination and unsolicited adverse events (AEs) were mild and similar among the three groups and resolved without sequelae. No serious AEs were notified up to 1 year post-vaccination. Four weeks post-vaccination, a slightly higher proportion of Group 1 subjects had a four-fold increase in SBA titers compared to Group 2 subjects (83% versus 72%, p>0.05). SBA GMTs in Groups 2 and 3 were higher than in Group 3 (p<0.05). Serogroup A-specific IgG GMCs were significantly higher in Group 1 than in Groups 2 (p<0.05) and 3 (p<0.05). After 1 year SBA titers were significantly higher in Group 1 than in Group 2 (p<0.05). The new PsA-TT vaccine was shown to be safe, immunogenic, and able to elicit persistent functional antibody titers in adults. This opens the prospective for further development and licensure of this vaccine to eliminate epidemic meningitis in sub-Saharan Africa.