Respiratory Syncytial Virus (RSV) Neutralizing Antibodies at Birth Predict Protection from RSV Illness in Infants in the First 3 Months of Life.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of viral pneumonia and bronchiolitis during the first 6 months of life. Placentally transferred antibodies can prevent severe RSV illness, and maternal immunization may reduce illness in young infants. Identification of protective antibody levels facilitates the advancement of vaccine candidates and maternal immunization. METHODS: We conducted a nested case-control study with 587 Malian mother-infant pairs, followed from birth to age 6 months. RSV cases were infants who developed influenza-like illness (ILI) or pneumonia and were RSV-positive by polymerase chain reaction. Cases were matched to healthy controls and RSV-negative ILI controls. RSV-A and RSV-B neutralizing antibodies were measured in maternal, cord blood, and infant sera at age 3 and 6 months. RESULTS: Maternal antibodies were efficiently transferred to infants. Maternal and infant RSV titers were strongly correlated. Infant antibody titers against RSV-A were 3 times higher than those against RSV-B. At birth, infants who remained healthy had significantly higher RSV-A and RSV-B titers compared with infants who subsequently contracted RSV. RSV-A inhibitory concentration (IC)80 titer >239 or RSV-B titer >60 at birth was significantly associated with being a healthy control compared with an RSV case within the first 3 months of life. RSV-A IC80 titers in cord blood were associated with decreased episodes of pneumonia. CONCLUSIONS: Maternally acquired RSV antibodies were associated with protection of infants against community-detected cases of RSV-ILI and pneumonia. RSV titers in cord blood can predict whether an infant will be infected with RSV or remain uninfected.

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).

A Phase 3, Double-Blind, Randomized, Active Controlled Study to Evaluate the Safety of MenAfriVac in Healthy Malians.

BACKGROUND: A safe, affordable, and highly immunogenic meningococcal A conjugate vaccine (PsA-TT, MenAfriVac) was developed to control epidemic group A meningitis in Africa. Documentation of the safety specifications of the PsA-TT vaccine was warranted, with sufficient exposure to detect potential rare vaccine-related adverse reactions. METHODS: This phase 3, double-blind, randomized, active controlled clinical study was designed to evaluate the safety--primarily vaccine-related serious adverse events (SAEs)--up to 3 months after administration of a single dose of the PsA-TT vaccine to subjects aged 1-29 years in Mali. Safety outcomes were also compared to those following a single dose of a licensed meningococcal ACWY polysaccharide vaccine (PsACWY). RESULTS: No vaccine-related SAEs occurred during the 3 months of follow-up of 4004 subjects vaccinated with a single dose of PsA-TT. When compared to PsACWY (1996 subjects), tenderness at the injection site appeared to be more frequent in the PsA-TT group. However, rates of local induration, systemic reactions, adverse events (AEs), and SAEs were similar in both groups, and unsolicited AEs and SAEs were all unrelated to the study vaccines. CONCLUSIONS: The study confirmed on a large scale the excellent safety profile of a single dose of PsA-TT when administered to its entire target population of 1-29 years of age. CLINICAL TRIALS REGISTRATION: PACTR ATMR201003000191317.

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).

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.

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.).

An Upsurge of Measles Cases in Mali-a Consequence of Pandemic-associated Disruption in Routine Immunization.

Measles deaths highlight immunization program gaps. In the Child Health and Mortality Prevention Surveillance study in Mali, we observed a rise in under-5 measles-related deaths in 2022 that corresponded with increased measles cases at the same time and a decline in measles vaccine coverage in Mali in 2020.

Safety and immunogenicity of a single dose of Tdap compared to Td in pregnant women in Mali and 3 its effect on infant immune responses: a single-centre, randomised, double-blind, active-controlled phase 2 study.

Background: While maternal pertussis vaccination is a strategy to reduce infant morbidity, safety and immunogenicity data are limited in sub-Saharan Africa. We aimed to evaluate the safety of a single dose of tetanus, diphtheria and acellular pertussis vaccine (Tdap) vaccine compared to tetanus and diphtheria vaccine (Td) vaccine in pregnant women in Bamako, Mali and to assess the pertussis toxin (PT) antibody response at birth. Methods: In this phase 2, single-centre, randomised, double-blind, active-controlled study, from 23 January 2019 to 10 July 2019, healthy 18-39 year old women in the second trimester of a singleton pregnancy were randomised 2:1 to receive Tdap or Td. Blood was tested for serum immunoglobulin G (IgG) against PT and other vaccine antigens using a qualified Meso Scale Discovery multiplex immunoassay. The co-primary objectives evaluated safety and birth anti-PT levels. Infant immune responses to whole-cell pertussis vaccine (DTwP) were assessed. Statistical analysis was descriptive. This trial is registered with clinicaltrials.gov, NCT03589768. Findings: 133 women received Tdap and 67 received Td, with 126 and 66 livebirths, respectively. In the Tdap group, 22 serious adverse events (SAEs) including one maternal death occurred in 20 participants (15·0%), with 10 SAEs in 10 participants (14·9%) in the Td group. Among infants, 18 events occurred among 13 participants (10.3%) and 8 SAEs in 6 participants (9.1%), including three and two infant deaths, occurred in Tdap and Td groups, respectively. None were related to study vaccines. Anti-PT geometric mean concentration (GMC) at birth in the Tdap group was higher than in the Td group (55.4 [46.2-66.6] IU/ml vs 7.9 [5.4-11.5] IU/ml). One month after the third dose of DTwP, the GMC in infants born to mothers in the Tdap group were lower compared to the Td group (20.2 [13.7-29.9] IU/ml vs 77.2 [32.2-184.8] IU/ml). By 6 months of age, the anti- PT GMCs were 17.3 [12.8-23.4] IU/ml and 67.1 [35.5-126.7] IU/ml in Tdap and Td groups, respectively. At birth, anti-tetanus toxin (TT) GMCs were higher in infants in the Td vs Tdap group (5.9 [5.0-7.0] IU/ml vs 4.1 [3.5-4.8] IU/ml). Anti-diphtheria toxin GMCs were similar in both groups. Interpretation: Tdap administered to pregnant women in Mali is safe and well-tolerated. Infants of mothers who received Tdap were born with high PT and protective anti-TT antibody levels. By six months of age, after primary vaccination, the PT levels were lower in the Tdap group compared to the Td group. The blunted immune responses to primary DTwP vaccination in the Tdap infant group warrant further study. Funding: This project was funded by National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), under contract numbers 75N93021C00012 (The Emmes Company), and HHSN27220130000221 (University of Maryland, Baltimore). Dr. Susana Portillo was supported by NIH award no. T32AI007524. NIAID, NIH provided Tdap vaccine (BOOSTRIX).

Antenatal, intrapartum and infant azithromycin to prevent stillbirths and infant deaths: study protocol for SANTE, a 2×2 factorial randomised controlled trial in Mali.

INTRODUCTION: In high mortality settings, prophylactic azithromycin has been shown to improve birth weight and gestational age at birth when administered antenatally, to reduce the incidence of neonatal infections when administered intrapartum, and to improve survival when administered in infancy. Questions remain regarding whether azithromycin can prevent stillbirths, and regarding the optimal strategy for the delivery of azithromycin to pregnant women and their infants. METHODS AND ANALYSIS: Sauver avec l'Azithromycine en Traitant les Femmes Enceintes et les Enfants (SANTE) is a 2×2 factorial, individually randomised, placebo-controlled, double-masked trial in rural Mali. The primary aims are: (1A) to assess the efficacy of antenatal and intrapartum azithromycin on a composite outcome of stillbirths and infant mortality through 6-12 months and (1B) to assess the efficacy of azithromycin administered concurrently with the first and third doses of pentavalent vaccines (Penta-1/3) on infant mortality through 6-12 months. Pregnant participants (n=49 600) and their infants are randomised 1:1:1:1 to one of four treatment arms: (1) mother and infant receive azithromycin, (2) mother and infant receive placebo, (3) mother receives azithromycin and infant receives placebo or (4) mother receives placebo and infant receives azithromycin. Pregnant participants receive three single 2 g doses: two antepartum and one intrapartum. Infants receive a single 20 mg/kg dose at the Penta-1 and 3 visits. An additional cohort of 12 000 infants is recruited at the Penta-1 visit and randomised 1:1 to receive azithromycin or placebo at the same time points. The SANTE trial will inform guidelines and policies regarding the administration of antenatal and infant azithromycin using routine healthcare delivery platforms. ETHICS AND DISSEMINATION: This trial was approved by the Institutional Review Board at the University of Maryland School of Medicine (Protocol #HP-00084242) and the Faculté de Médecine et d'Odonto-Stomatologie in Mali. The findings of this trial will be published in open access peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03909737.

Safety and immunogenicity of quadrivalent meningococcal polysaccharide vaccine (MPV ACYW135) compared with quadrivalent meningococcal conjugate vaccine (Menactra®) in Malian children.

Affordable, polyvalent meningococcal vaccines are needed for use in emergency reactive immunization campaigns. A phase IV randomized, observer-blind, controlled study compared the safety and immunogenicity of a quadrivalent meningococcal polysaccharide vaccine (MPV-4, MPV ACYW135) and quadrivalent meningococcal ACWY conjugate vaccine (MCV-4, Menactra®). Healthy, 2- to 10-year-old children in Bamako, Mali, were randomized 1:1 to receive one dose of MPV-4 or MCV-4. Safety outcomes were evaluated for 6 months post-immunization. Immunogenicity for all serogroups was assessed for non-inferiority between MPV-4 and MCV-4 30 days post immunization by serum bactericidal antibody assay using baby rabbit complement (rSBA). From December 2020 to July 2021, 260 healthy subjects were consented and randomized. At Day 30 post-immunization, the proportions of subjects with rSBA titers ≥ 128 for all serogroups in the MPV-4 group were non-inferior to those in MCV-4 group. The proportions of subjects with rSBA ≥ 4-fold increase and rSBA titers ≥ 8 for all serogroups were similar among vaccine groups (P > .05). Geometric Mean Titers and Geometric Mean Fold Increases for all serogroups in both vaccine groups were similar (P > .05). Few local and systemic post-immunization reactions of similar severity and duration were observed within 7 days and were similar in both groups (P > .05). All resolved without sequelae. Unsolicited adverse events were similar in both groups regarding relationship to study vaccine, severity and duration. No serious adverse events were reported during the study period. MPV ACYW135 showed a non-inferior immunogenicity profile and a comparable reactogenicity profile to MCV-4 in Malian children aged 2-10 years.Clinical Trial Registration: NCT04450498.