Ethical Challenges and Lessons Learned During the Clinical Development of a Group A Meningococcal Conjugate Vaccine.

BACKGROUND: The group A meningococcal vaccine (PsA-TT) clinical development plan included clinical trials in India and in the West African region between 2005 and 2013. During this period, the Meningitis Vaccine Project (MVP) accumulated substantial experience in the ethical conduct of research to the highest standards. METHODS: Because of the public-private nature of the sponsorship of these trials and the extensive international collaboration with partners from a diverse setting of countries, the ethical review process was complex and required strategic, timely, and attentive communication to ensure the smooth review and approval for the clinical studies. Investigators and their site teams fostered strong community relationships prior to, during, and after the studies to ensure the involvement and the ownership of the research by the participating populations. As the clinical work proceeded, investigators and sponsors responded to specific questions of informed consent, pregnancy testing, healthcare, disease prevention, and posttrial access. RESULTS: Key factors that led to success included (1) constant dialogue between partners to explore and answer all ethical questions; (2) alertness and preparedness for emerging ethical questions during the research and in the context of evolving international ethics standards; and (3) care to assure that approaches were acceptable in the diverse community contexts. CONCLUSIONS: Many of the ethical issues encountered during the PsA-TT clinical development are familiar to groups conducting field trials in different cultural settings. The successful approaches used by the MVP clinical team offer useful examples of how these problems were resolved. CLINICAL TRIALS REGISTRATION: ISRCTN17662153 (PsA-TT-001); ISRTCN78147026 (PsA-TT-002); ISRCTN87739946 (PsA-TT-003); ISRCTN46335400 (PsA-TT-003a); ISRCTN82484612 (PsA-TT-004); CTRI/2009/091/000368 (PsA-TT-005); PACTR ATMR2010030001913177 (PsA-TT-006); PACTR201110000328305 (PsA-TT-007).

Community Perspectives Associated With the African PsA-TT (MenAfriVac) Vaccine Trials.

BACKGROUND: The Meningitis Vaccine Project (MVP) was established to address epidemic meningitis as a public health problem in sub-Saharan Africa and, to that end, worked to develop a group A meningococcal conjugate vaccine, PsA-TT. METHODS: Experiences in 4 clinical trial sites are described. Culturally sensitive collaborative strategies were adopted to manage acceptable communication methods, peculiarities with the consent process, participant medical issues, community care, and death. RESULTS: The clinical trials were completed successfully through community acceptance and active community collaboration. The trials also strengthened the capacities in the participating communities, and actively worked to resolve community problems. CONCLUSIONS: The understanding and integration of sociocultural realities of communities were major assets in the conduct and acceptance of these trials. MVP succeeded in these sites and provided a sound example for future clinical studies in Africa. CLINICAL TRIALS REGISTRATION: ISRTCN78147026 (PsA-TT 002); ISRCTN87739946 (PsA-TT 003); ISRCTN82484612 (PsA-TT 004); PACTR ATMR2010030001913177 (PsA-TT 006); and PACTR201110000328305 (PsA-TT 007).

Antibody Persistence 1-5 Years Following Vaccination With MenAfriVac in African Children Vaccinated at 12-23 Months of Age.

BACKGROUND: Following mass vaccination campaigns in the African meningitis belt with group A meningococcal conjugate vaccine, MenAfriVac (PsA-TT), disease due to group A meningococci has nearly disappeared. Antibody persistence in healthy African toddlers was investigated. METHODS: African children vaccinated at 12-23 months of age with PsA-TT were followed for evaluation of antibody persistence up to 5 years after primary vaccination. Antibody persistence was evaluated by measuring group A serum bactericidal antibody (SBA) with rabbit complement and by a group A-specific IgG enzyme-linked immunosorbent assay (ELISA). RESULTS: Group A antibodies measured by SBA and ELISA were shown to decline in the year following vaccination and plateaued at levels significantly above baseline for up to 5 years following primary vaccination. CONCLUSIONS: A single dose of PsA-TT induces long-term sustained levels of group A meningococcal antibodies for up to 5 years after vaccination. CLINICAL TRIALS REGISTRATION: ISRTCN78147026.

Antibody Persistence at 1 and 4 Years Following a Single Dose of MenAfriVac or Quadrivalent Polysaccharide Vaccine in Healthy Subjects Aged 2-29 Years.

BACKGROUND: Mass vaccination campaigns of the population aged 1-29 years with 1 dose of group A meningococcal (MenA) conjugate vaccine (PsA-TT, MenAfriVac) in African meningitis belt countries has resulted in the near-disappearance of MenA. The vaccine was tested in clinical trials in Africa and in India and found to be safe and highly immunogenic compared with the group A component of the licensed quadrivalent polysaccharide vaccine (PsACWY). Antibody persistence in Africa and in India was investigated. METHODS: A total of 900 subjects aged 2-29 years were followed up for 4 years in Senegal, Mali, and The Gambia (study A). A total of 340 subjects aged 2-10 years were followed up for 1 year in India (study B). In study A, subjects were randomized in a 2:1 ratio, and in study B a 1:1 ratio to receive either PsA-TT or PsACWY. Immunogenicity was evaluated by measuring MenA serum bactericidal antibody (SBA) with rabbit complement and by a group A-specific immunoglobulin G (IgG) enzyme-linked immunosorbent assay. RESULTS: In both studies, substantial SBA decay was observed at 6 months postvaccination in both vaccine groups, although more marked in the PsACWY group. At 1 year and 4 years (only for study A) postvaccination, SBA titers were relatively sustained in the PsA-TT group, whereas a slight increasing trend, more pronounced among the youngest, was observed in the participants aged <18 years in the PsACWY groups. The SBA titers were significantly higher in the PsA-TT group than in the PsACWY group at any time point, and the majority of subjects in the PsA-TT group had SBA titers ≥128 and group A-specific IgG concentrations ≥2 µg/mL at any point in time in both the African and Indian study populations. CONCLUSIONS: Four years after vaccination with a single dose of PsA-TT vaccine in Africa, most subjects are considered protected from MenA disease. CLINICAL TRIALS REGISTRATION: PsA-TT-003 (ISRCTN87739946); PsA-TT-003a (ISRCTN46335400).

The impact of pre-existing antibody on subsequent immune responses to meningococcal A-containing vaccines.

Major epidemics of serogroup A meningococcal meningitis continue to affect the African meningitis belt. The development of an affordable conjugate vaccine against the disease became a priority for World Health Organization (WHO) in the late 1990s. Licensing of meningococcal vaccines has been based on serological correlates of protection alone, but such correlates might differ in different geographical regions. If high pre-vaccination antibody concentrations/titers impacts on the response to vaccination and possibly vaccine efficacy, is not clearly understood. We set out to define the pre-vaccination Meningococcal group A (Men A) antibody concentrations/titers in The Gambia and study their impact on the immunogenicity of Men A containing vaccines. Data from subjects originally enrolled in studies to test the safety and immunogenicity of the MenA vaccine recently developed for Africa meningococcal A polysaccharide conjugated to tetanus toxoid, MenAfriVac(®) (PsA-TT) were analyzed. Participants had been randomized to receive either the study vaccine PsA-TT or the reference quadrivalent plain polysaccharide vaccine containing meningococcal groups A, C, W, and Y, Mencevax(®) ACWY, GlaxoSmithKline (PsACWY) in a 2:1 ratio. Venous blood samples were collected before and 28 days after vaccination. Antibodies were assayed by enzyme-linked immunosorbent assay (ELISA) for geometric mean concentrations and serum bactericidal antibody (SBA) for functional antibody. The inter age group differences were compared using ANOVA and the pre and post-vaccination differences by t test. Over 80% of the ≥19 year olds had pre-vaccination antibody concentrations above putatively protective concentrations as compared to only 10% of 1-2 year olds. Ninety-five percent of those who received the study vaccine had ≥4-fold antibody responses if they had low pre-vaccination concentrations compared to 76% of those with high pre-vaccination concentrations. All subjects with low pre-vaccination titers attained ≥4-fold responses as compared to 76% with high titers where study vaccine was received. Our data confirm the presence of high pre-vaccination Men A antibody concentrations/titers within the African meningitis belt, with significantly higher concentrations in older individuals. Although all participants had significant increase in antibody levels following vaccination, the four-fold or greater response in antibody titers were significantly higher in individuals with lower pre-existing antibody titers, especially after receiving PsA-TT. This finding may have some implications for vaccination strategies adopted in the future.

High genotypic diversity among rotavirus strains infecting Gambian children.

BACKGROUND: Rotavirus is the leading cause of diarrhea in children <5 years of age. In light of the implementation of rotavirus vaccines of limited valency, it is important to characterize the genotypic diversity of circulating rotavirus in sub-Saharan Africa. METHODS: We collected stool samples from children 0-59 months of age who presented at the health centres as cases with moderate-to-severe diarrhea in the Upper River Region of The Gambia. Stool samples were also collected from age, sex and area-matched healthy controls. All stool samples were assayed for rotavirus antigens by enzyme-linked immunosorbent assay and genotyping was done using reverse transcriptase polymerase chain reaction. RESULTS: We enrolled 1029 cases and 1569 controls during the 3-year study period (2008-2010). The detection rate of rotavirus among the cases was 20% (204/1029) and 3% (42/1569) among controls. At least 18 genotypes were found and the predominant genotypes were G2P[6] (28%), G1P[8] (26%) and G1P[10] (10%). The rare identified genotypes (<1%) were G2P[14], G8P[6], G9P[6] and G4P[10]. There was also a strong positive association between rotavirus infection and the dry season (odds ratio: 9.83, 95% confidence interval: 6.18-15.63, P < 0.001). A significant increase in the odds of rotavirus and G1P[8] detection with the use of untreated water and the presence of cats, rodents and cows in the child's residence was also found. CONCLUSION: This study provides important baseline data for the genotypes circulating before vaccine implementation. The wide diversity of genotypes circulating in The Gambia implies the need for vigilant effectiveness surveillance following the implementation of RotaTeq in August 2013.

Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study.

BACKGROUND: Diarrhoeal diseases cause illness and death among children younger than 5 years in low-income countries. We designed the Global Enteric Multicenter Study (GEMS) to identify the aetiology and population-based burden of paediatric diarrhoeal disease in sub-Saharan Africa and south Asia. METHODS: The GEMS is a 3-year, prospective, age-stratified, matched case-control study of moderate-to-severe diarrhoea in children aged 0-59 months residing in censused populations at four sites in Africa and three in Asia. We recruited children with moderate-to-severe diarrhoea seeking care at health centres along with one to three randomly selected matched community control children without diarrhoea. From patients with moderate-to-severe diarrhoea and controls, we obtained clinical and epidemiological data, anthropometric measurements, and a faecal sample to identify enteropathogens at enrolment; one follow-up home visit was made about 60 days later to ascertain vital status, clinical outcome, and interval growth. FINDINGS: We enrolled 9439 children with moderate-to-severe diarrhoea and 13,129 control children without diarrhoea. By analysing adjusted population attributable fractions, most attributable cases of moderate-to-severe diarrhoea were due to four pathogens: rotavirus, Cryptosporidium, enterotoxigenic Escherichia coli producing heat-stable toxin (ST-ETEC; with or without co-expression of heat-labile enterotoxin), and Shigella. Other pathogens were important in selected sites (eg, Aeromonas, Vibrio cholerae O1, Campylobacter jejuni). Odds of dying during follow-up were 8·5-fold higher in patients with moderate-to-severe diarrhoea than in controls (odd ratio 8·5, 95% CI 5·8-12·5, p<0·0001); most deaths (167 [87·9%]) occurred during the first 2 years of life. Pathogens associated with increased risk of case death were ST-ETEC (hazard ratio [HR] 1·9; 0·99-3·5) and typical enteropathogenic E coli (HR 2·6; 1·6-4·1) in infants aged 0-11 months, and Cryptosporidium (HR 2·3; 1·3-4·3) in toddlers aged 12-23 months. INTERPRETATION: Interventions targeting five pathogens (rotavirus, Shigella, ST-ETEC, Cryptosporidium, typical enteropathogenic E coli) can substantially reduce the burden of moderate-to-severe diarrhoea. New methods and accelerated implementation of existing interventions (rotavirus vaccine and zinc) are needed to prevent disease and improve outcomes. FUNDING: The Bill & Melinda Gates Foundation.

Health Care Utilization and Attitudes Survey: understanding diarrheal disease in rural Gambia.

Diarrheal disease causes ∼1.34 million deaths per year among children under 5 years of age globally. We conducted a Health Care Utilization and Attitudes Survey of 1,012 primary caregivers of children aged 0-11, 12-23, and 24-59 months randomly selected from a Demographic Surveillance population in rural Gambia. Point prevalence of diarrhea was 7.7% (95% confidence interval [CI] = 6.1-9.8); 23.3% had diarrhea within the previous 2 weeks. Caregivers of 81.5% of children with diarrhea sought healthcare outside their home, but only 48.4% of them visited a health center. Only 17.0% (95% CI = 12.1-23.2) of children with diarrhea received oral rehydration solution (ORS) at home. Abbreviated surveys conducted on six occasions over the subsequent 2 years showed no change in prevalence or treatment-seeking behavior. Diarrhea remains a significant problem in rural young Gambian children. Encouraging care-seeking behavior at health centers and promoting ORS use can reduce mortality and morbidity in this population.

Pneumococcal antibody concentrations and carriage of pneumococci more than 3 years after infant immunization with a pneumococcal conjugate vaccine.

BACKGROUND: A 9-valent pneumococcal conjugate vaccine (PCV-9), given in a 3-dose schedule, protected Gambian children against pneumococcal disease and reduced nasopharyngeal carriage of pneumococci of vaccine serotypes. We have studied the effect of a booster or delayed primary dose of 7-valent conjugate vaccine (PCV-7) on antibody and nasopharyngeal carriage of pneumococci 3-4 years after primary vaccination. METHODOLOGY/PRINCIPAL FINDINGS: We recruited a subsample of children who had received 3 doses of either PCV-9 or placebo (controls) into this follow-up study. Pre- and post- PCV-7 pneumococcal antibody concentrations to the 9 serotypes in PCV-9 and nasopharyngeal carriage of pneumococci were determined before and at intervals up to 18 months post-PCV-7. We enrolled 282 children at a median age of 45 months (range, 38-52 months); 138 had received 3 doses of PCV-9 in infancy and 144 were controls. Before receiving PCV-7, a high proportion of children had antibody concentrations >0.35 µg/mL to most of the serotypes in PCV-9 (average of 75% in the PCV-9 and 66% in the control group respectively). The geometric mean antibody concentrations in the vaccinated group were significantly higher compared to controls for serotypes 6B, 14, and 23F. Antibody concentrations were significantly increased to serotypes in the PCV-7 vaccine both 6-8 weeks and 16-18 months after PCV-7. Antibodies to serotypes 6B, 9V and 23F were higher in the PCV-9 group than in the control group 6-8 weeks after PCV-7, but only the 6B difference was sustained at 16-18 months. There was no significant difference in nasopharyngeal carriage between the two groups. CONCLUSIONS/SIGNIFICANCE: Pneumococcal antibody concentrations in Gambian children were high 34-48 months after a 3-dose primary infant vaccination series of PCV-9 for serotypes other than serotypes 1 and 18C, and were significantly higher than in control children for 3 of the 9 serotypes. Antibody concentrations increased after PCV-7 and remained raised for at least 18 months.

Meningococcal group C and w135 immunological hyporesponsiveness in african toddlers.

A phase II clinical study was conducted in African toddlers (aged 12 to 23 months), with subjects receiving either investigational meningococcal group A conjugate (PsA-TT), meningococcal ACWY polysaccharide (PsACWY), or Haemophilus influenzae type b (Hib-TT) vaccine. Ten months following vaccination, the 3 study groups were further randomized to receive a dose of PsA-TT, a 1/5 dose of PsACWY, or a dose of Hib-TT vaccine. Group A serum bactericidal antibody (SBA) results have been reported previously, with PsA-TT demonstrating superior immunogenicity versus PsACWY vaccine. Immunogenicity for serogroups W135 and C was assessed by SBA assay to investigate the impact of multiple doses in this age group. Blood samples were taken prior to vaccination, 28 days and 40 weeks post-primary vaccination, and 7 and 28 days post-booster vaccination with a 1/5 dose of PsACWY. Subjects who had previously received a full dose of PsACWY had W135 SBA geometric mean titers (GMTs) of 26.1 and 4.4 at 7 and 28 days post-booster vaccination with a 1/5 PsACWY dose, respectively, whereas the W135 SBA GMTs of naïve subjects at these time points following vaccination with a 1/5 dose of PsACWY were 861.1 and 14.6, respectively. Similar differences were observed for serogroup C, with SBA GMTs of 99 and 5.9 at 7 and 28 days post-booster vaccination with a 1/5 dose of PsACWY, respectively, for naïve subjects, compared to 4.1 and 3.2 for previously vaccinated subjects. Immunologic hyporesponsiveness for groups C and W135 was observed following a full dose of PsACWY vaccine at 12 to 23 months of age and a 1/5 dose of PsACWY 10 months later compared to the case for PsACWY-naïve subjects receiving a 1/5 dose of PsACWY vaccine.

Immunogenicity and safety of a meningococcal A conjugate vaccine in Africans.

BACKGROUND: Group A meningococci are the source of major epidemics of meningitis in Africa. An affordable, highly immunogenic meningococcal A conjugate vaccine is needed. METHODS: We conducted two studies in Africa to evaluate a new MenA conjugate vaccine (PsA-TT). In study A, 601 children, 12 to 23 months of age, were randomly assigned to receive PsA-TT, a quadrivalent polysaccharide reference vaccine (PsACWY), or a control vaccine (Haemophilus influenzae type b conjugate vaccine [Hib-TT]). Ten months later, these children underwent another round of randomization within each group to receive a full dose of PsA-TT, a one-fifth dose of PsACWY, or a full dose of Hib-TT, with 589 of the original participants receiving a booster dose. In study B, 900 subjects between 2 and 29 years of age were randomly assigned to receive PsA-TT or PsACWY. Safety and reactogenicity were evaluated, and immunogenicity was assessed by measuring the activity of group A serum bactericidal antibody (SBA) with rabbit complement and performing an IgG group A-specific enzyme-linked immunosorbent assay. RESULTS: In study A, 96.0% of the subjects in the PsA-TT group and 63.7% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline; in study B, 78.2% of the subjects in the PsA-TT group and 46.2% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline. The geometric mean SBA titers in the PsA-TT groups in studies A and B were greater by factors of 16 and 3, respectively, than they were in the PsACWY groups (P<0.001). In study A, the PsA-TT group had higher antibody titers at week 40 than the PsACWY group and had obvious immunologic memory after receiving a polysaccharide booster vaccine. Safety profiles were similar across vaccine groups, although PsA-TT recipients were more likely than PsACWY recipients to have tenderness and induration at the vaccination site. Adverse events were consistent with age-specific morbidity in the study areas; no serious vaccine-related adverse events were reported. CONCLUSIONS: The PsA-TT vaccine elicited a stronger response to group A antibody than the PsACWY vaccine. (Funded by the Meningitis Vaccine Project through a grant from the Bill and Melinda Gates Foundation; Controlled-Trials.com numbers, ISRCTN78147026 and ISRCTN87739946.).

The immunogenicity and impact on nasopharyngeal carriage of fewer doses of conjugate pneumococcal vaccine immunization schedule.

The immunogenicity and impact on carriage of fewer doses of pneumococcal conjugate vaccine (PCV7) followed by booster with pneumococcal polysaccharide vaccine (PPV) were investigated. 684 infants were assigned randomly to one of the three groups that received one (A), two (B) or three (C) doses of PCV7 between 2 and 4 months of age, plus PPV at 10 months. Following primary vaccination protective antibody titers of >0.35 µg/ml against the PCV7 serotypes combined increased significantly with the number of PCV7 doses, 44% vs. 77% vs. 94% (p<0.001), and correlated positively with the opsonophagocytic indices, but negatively with nasopharyngeal carriage of pneumococcus. The differences in antibody responses and pneumococcal carriage between the groups diminished following booster with PPV, implying that administration of one or two doses of PCV7, with a booster dose of PPV might lower the cost of protection against IPD in young children in resource poor countries.

Contents of referral letters to the children emergency unit of a teaching hospital, southwest of Nigeria.

OBJECTIVE: This study was carried out to evaluate the quality of the contents of referral letters received at the pediatric emergency unit of the University College Hospital, Ibadan, Nigeria. DESIGN: We prospectively reviewed consecutive referral letters received over a 6-month period. The details of the contents of each letter were recorded using a structured pro-forma by 2 of the investigators after consent was obtained from the parent or caregiver. RESULTS: There were 974 patients admitted with referral letters; this accounted for 54.8% of all admissions. There were 568 boys and 406 girls (ratio, 1.4:1). More than one tenth of the referred patients reported after 24 hours of writing the letters. Letters were written by physicians (69.2%), registered nurses (21.3%), hospital assistants (2.1%), traditional birth attendants (0.4%), and non-health workers (0.3%). The identity of the writers of 65 letters (6.7%) could not be defined. More than half of the letters did not contain the patients' age, the treatment given, the findings from the investigations performed, the medical history, and what the writers expect from the referral. Other missing information includes examination findings (47.9%), provisional diagnosis (38.6%), history of presenting complaints (36.6%), writers' addresses (32.5%), reasons for the referral (23.9%), patients' sex (20.1%), and patients' names (3.4%). The most frequently stated reason for referral was poor or no response to the treatment given (17.8%). CONCLUSION: The contents of referral letters from the general practitioners to the pediatric emergency unit were found to be grossly inadequate. To enhance the quality of correspondence between the referring physicians and pediatricians, there may be a need for training and introduction of letter-format prompt forms.