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Determining the dose-response relationship for pneumococcal conjugate vaccines: a nested analysis of the fractional
Irene Martinez-de-Albeniz1, Christian Bottomley1, Ruth Lucinde2
1Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Insights
Fractional doses of pneumococcal conjugate vaccines (PCV10/13) elicit varied immune responses in infants. Dose, vaccine type, and individual factors influence IgG concentrations, suggesting potential for optimized vaccine formulation.
Area of Science:
- Immunology
- Vaccinology
- Pediatrics
Background:
- The dose-response relationship for pneumococcal conjugate vaccines (PCV) remains undefined.
- A randomized trial in Kenyan infants assessed fractional PCV10 and PCV13 doses against full doses.
- The study aimed to elucidate serotype-specific dose-response patterns and influencing factors.
Purpose of the Study:
- To establish the relationship between polysaccharide dose and immune response to PCV10 and PCV13.
- To identify factors affecting immune responses after vaccination in infants.
- To determine optimal fractional dosing strategies for PCV.
Main Methods:
- Analysis of data from 1342 infants receiving 20%, 40%, or full PCV doses at 6 and 14 weeks.
- Mixed-effects linear regression models to assess dose-response relationships and influencing factors.
- Logistic regression to estimate the minimum dose for a protective immune response.
Main Results:
- Polysaccharide dose, vaccine type, infant ethnicity, sex, maternal age, and dosing interval impacted IgG concentrations.
- PCV13 showed quadratic dose-response for most serotypes, while PCV10 exhibited linear or log-dose relationships for different serotypes.
- Specific serotypes demonstrated distinct dose-response curves for both PCV10 and PCV13.
Conclusions:
- Infant immune responses to PCV10/13 are dose-dependent and influenced by multiple factors.
- Findings support the potential for reformulating PCV10/13 to enhance protective immune responses.
- Optimizing vaccine composition and dosage could improve efficacy in infant populations.
Background:
The relationship between polysaccharide dose and immune response to pneumococcal conjugate vaccines (PCV) has never been established. An individually randomized controlled clinical trial was conducted in Kenyan infants to assess whether immune responses after fractional doses of PCV10 (Synflorix, GlaxoSmithKline plc.) or PCV13 (Prevnar13, Pfizer Inc.) were non-inferior to full-dose schedules (ClinicalTrials.org: NCT03489018; Pan African Clinical Trial Registry: PACTR202104717648755). We analysed these data to describe the serotype-specific dose-response relationships and evaluate factors associated with the immune response.
Methods:
We analysed data from participants who received PCV doses at 6 and 14 weeks of age, with immunogenicity assessed at 18 weeks of age. Participants received 20 %, 40 % or full doses of PCV10 or PCV13. We used mixed-effects linear regression models to estimate the dose-response relationships between polysaccharide dose and log-transformed IgG concentrations and to determine factors associated with immune response. We estimated the minimum dose required to obtain a high (≥95 %) probability of an immunological response above the level considered to be associated with protection using logistic regression.
Results:
1342 infants were included. The polysaccharide dose, product, child's ethnicity, sex, maternal age, and interval between second PCV dose and immunogenicity sample were independently associated with IgG concentrations elicited by the primary schedule. For PCV13, the relationship between dose and log(IgG) was best described by a quadratic function for serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 19A and 23F, whereas a log-dose model was the best fit for serotypes 14, 18C and 19F. For PCV10, a linear relationship was the best fit for serotypes 1, 6B, 7F, 9V and 23F and log-dose model was the best fit for 4, 5, 14, 18C and 19F.
Conclusion:
Our findings suggest that available PCV10/13 could be reformulated to optimize protective responses.
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