Maternal Immunization With MenAfriVac™

Meningitis Clinical Trial

Official title: Maternal Immunization With MenAfriVac™

Status Active, not recruiting

Clinical Trial Summary

The World Health Organization (WHO) recommends that infants receive a single dose of the meningococcal serogroup A-tetanus toxoid conjugate vaccine, MenAfriVac, when they reach at least 9 months of age. However, this leaves a window of susceptibility in early life when the incidence of invasive serogroup A disease, and the case fatality rate for the condition is at its highest. This study will investigate the potential role of administering the vaccine to expectant mothers at the start of the third trimester of pregnancy in order to protect their subsequent borne infants. Antibody transfer to the newborn and subsequent antibody decay will be measured. The level of protection against neonatal tetanus provided by the tetanus toxoid component of the vaccine, when compared to the routine dose of tetanus administered in pregnancy will also be assessed.

As a separate exploratory study, the follow-up of the cohort planned will also be used to investigate the effects that the development of the gastrointestinal microbiome, and any perturbations in the microbiome caused by antibiotic use, have on immune development and vaccine immunogenicity over the first 10 months of life.

Clinical Trial Description

MenAfriVac is a Neisseria meningitidis serogroup A Men A polysaccharide-tetanus toxoid conjugate vaccine which was developed within the space of just nine years through the Meningitis Vaccine Project. Although the effectiveness of the vaccine is well established, the optimum strategy for maintaining protection following the mass vaccination campaigns has yet to be determined. However, in mathematical models, even considering a coverage rate of as low as 60 percent, the routine administration of MenAfriVac nine-months results in a lower annual disease incidence than regular campaigns targeting one to four year old children. Thus, the introduction of a single dose of MenAfriVac® at nine to 18 months in meningitis belt has subsequently been recommended by the WHO.

An important limitation of such a regimen is that infants are left without direct protection against Men A infection up to the age of at least nine months. While not classically considered to be a disease of early infancy, the incidence of invasive Men A infection is as high or higher in this age group as compared to the incidence in older children and the case fatality rate is also at its peak under the age of one. Recent mass vaccination campaigns rapidly achieved exceptionally high levels of coverage across the entire one to 29 year old adult population and have resulted in herd protection and reduced level of invasive disease in those under one year of age. However, such levels of herd protection cannot be assumed following routine scheduling at nine months of age and thus alternative strategies both to protect the infant up to nine months of age and also to boost herd protection in the population warrant exploration.

Maternal immunization represents a potentially attractive option with both regards. The safety of the vaccine when administered in pregnancy has been assessed through comparing the rate of safety events in 1730 expectant mothers immunized during campaigns in the Navrongo region of Ghana, and their subsequent born infants with the rates in the women who did not receive the vaccine during the same campaign (n=919) and those vaccinated the previous year (n=3551). No evidence of any safety concerns were reported. These data support current WHO technical guidance which considers it safe to include pregnant and lactating women within mass vaccination campaigns. Although the safety profile is reassuring, there are currently no data on the immunogenicity of MenAfriVac in pregnancy or on the transplacental transfer of Men A specific antibodies to subsequent borne infants. In addition, the comparability of the tetanus toxoid specific seroprotection provided to the newborn through the tetanus toxoid carrier protein and through the standard tetanus toxoid antenatal booster needs to be established.

Within the Protecting from Pneumococcus in Early Life (PROPEL) trial (NCT02628886) trial a group of 200 expectant mothers were randomized into the control group and received tetanus toxoid (and a 0.9% sodium chloride injection to maintain blinding) at 28 to 34 weeks gestation. This group will serve as a control group for the MenAfriVac vaccinated mothers who will be recruited here using an otherwise identical protocol. Those mothers confirmed to be eligible (n = 100) will receive a dose of MenAfriVac at 28 to 34 weeks of gestation and will subsequently followed up using the same approach as undertaken in the PROPEL trial. Their subsequent born infants will also be followed until nine months of age in the same way. Maternal and cord blood samples will be collected at delivery with peripheral infant samples being obtained at delivery, 8 and 20 weeks and at 9 months plus 9 months 4 weeks. The meningococcal serogroup A and tetanus toxoid specific seroprotection in the infants of mothers vaccinated with MenAfriVac will be compared to the seroprotection in those mothers in the control group for the main randomized trial who will only have received tetanus toxoid in pregnancy. All safety procedures will be undertaken in the same way for comparability.

Most mothers in the study will have been immunized in the national MenAfriVac campaign in the Gambia in Nov/Dec 2013, so the controls will not be naïve, and the MenAfriVac arm will be receiving a second dose of the vaccine. This reflects the likely situation were maternal immunization to be recommended in the future. Information on prior immunization history will be collected and assessed within the statistical analysis.

Exploratory nested study:

The study provides an opportunity to monitor the development of the intestinal microbiome from birth to 10 months of age and to assess the effects that any antibiotics, administered in early life for clinical indication, have on this development. Furthermore, to study the downstream effects of distinct microbial profiles on baseline and post-vaccination transcriptomic and metabolomic profiles and immune cell phenotypes, and on the serological responses to vaccination.

The gastrointestinal microbiome is at its most dynamic in early life from the point of first colonization at birth. It is also the period during which parenteral empirical antibiotics are most likely to be administered given the difficulty in excluding invasive bacterial diseases at this age. Thus, early infancy provides the best possible opportunity to study the effects of the microbiome, including of any disruption in the microbiome driven by antibiotic therapy, on baseline (unstimulated) and post-vaccination transcriptomic and metabolomic profiles, immune cell phenotypes and serological response to vaccination.

This component of the study is observational and exploratory. All 100 infants will be administered the routine vaccines in the national schedule due at the time points they are routinely given. Associations between the development of the microbiome with transcriptional and metabolomics signatures, cellular and serological responses to vaccination will be made within group. ;

Related Conditions & MeSH terms

• Meningitis
• Meningococcal

• NCT number: NCT03746665
• Study type: Interventional
• Source: London School of Hygiene and Tropical Medicine
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: December 19, 2018
• Completion date: August 2021