Vaccine-induced responses to R21/Matrix-M - an analysis of samples from a phase 1b age de-escalation, dose-escalation
Caroline Bundi1,2, Duncan Bellamy3, Elizabeth Kibwana1
1Centre for Geographic Medicine Research, Coast, Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya.
Insights
The R21 malaria vaccine is effective in children, but antibody responses vary by age and adjuvant dose. Further research is needed to optimize next-generation malaria vaccines.
Area of Science:
- Immunology
- Vaccinology
- Infectious Diseases
Background:
- The R21 malaria vaccine, adjuvanted with Matrix-M, shows promise with 75% efficacy in Phase 3 trials and WHO recommendation for young children.
- Antibodies targeting NANP are linked to protection, but factors like age and prior immunity influence vaccine responses.
Purpose of the Study:
- To assess R21/Matrix-M vaccine-induced antibody quantity and function across different age groups (adults, children, infants).
- To investigate the impact of age, vaccine dose, and pre-existing immunity on R21 vaccine immunogenicity.
Main Methods:
- Antibody levels and function (complement fixation, sporozoite invasion inhibition, avidity) were measured in participants from a Phase 1 R21/Matrix-M trial.
- Pre-existing malaria exposure was assessed using ELISA, and anti-HBsAg IgG levels were monitored.
Main Results:
- R21/Matrix-M induced functional antibodies (CSP antibodies) that were lower in adults than in children and infants.
- Higher adjuvant dose correlated with increased complement fixation and sporozoite invasion inhibition in infants.
- Age and vaccine dose significantly influenced antibody magnitude and function, while avidity was not consistently associated with protection.
Conclusions:
- R21/Matrix-M is immunogenic across age groups, with age and adjuvant dose being critical factors influencing antibody responses.
- Optimizing adjuvant and vaccine dose is crucial for advancing malaria vaccine development.
- Further research is necessary to fully understand factors influencing R21 vaccine efficacy and to inform next-generation malaria vaccines.
Introduction:
The pre-erythrocytic malaria vaccine R21 vaccine adjuvanted with Matrix-M reported good efficacy (75%) in an ongoing phase 3 trial and was recommended World Health Organization for use in children 5-36 months. Vaccine-induced antibodies against NANP are associated with protection, however, various factors such as age, pre-existing immunity, and vaccine dose have been shown to influence vaccine responses.
Methods:
Samples from adults (n =18), children (n = 17), and infants (n = 51) vaccinated with R21/Matrix-M in a phase I trial were assayed for vaccine-specific antibody responses. We measured antibodies (quantity) by MSD and ELISA; and function (quality) by complement (C1q) fixation assay, inhibition of sporozoite invasion (ISI) assay, and avidity assay. Pre-existing malaria antibody exposure was assessed using an anti-3D7 Plasmodium falciparum crude parasite lysate ELISA.
Results:
Vaccine-induced CSP antibodies (against full-length R21, NANP, and C terminus), exhibited complement fixation and inhibition of sporozoites. These were significantly lower in adults compared to children and infants. Additionally, children had a higher rate of decay of vaccine-induced antibodies compared to adults 2 years post-vaccination. Furthermore, a higher Matrix-M adjuvant dose resulted in significantly higher C1q fixation, and ISI than the low adjuvant dose in infants. Importantly, functional measures ISI and C1q-fixation were positively associated with the vaccine-induced antibodies overall, but avidity was not. Interestingly, in adults, previous malaria exposure was negatively associated with ISI but positively correlated with avidity and C1q fixation. At baseline, all the study participants were seropositive for anti-HBsAg IgG above the WHO-required protective threshold of 10 mIU/mL, and titers significantly increased post-vaccination.
Discussion:
R21/Matrix-M was immunogenic across all age groups, with age and vaccine dose significantly affecting antibody magnitude and function. These findings emphasize the importance of evaluating the right adjuvant and vaccine dose for clinical development progression. This could thus inform the development of next-generation malaria vaccines. However, additional crucial factors need further exploration.
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