2021-04-27 13:27:49

Introduction

  • Antigen dose is an important determinant of vaccines.
  • A universal flu vaccine needs to induce strong and broad responses. Dose likely impacts both strength and breadth.
  • For influenza, there is currently a high-dose (HD) vaccine approved for those >=65 years of age.
  • HD has been shown to induce higher immunogenicity and protection against vaccine strains.
  • Impact of dose on heterologous responses is uncertain.

Goals

  • Long-term: Better understand and optimize dose toward inducing strong and broad immune protection. Use this knowledge as part of the COBRA vaccine development process.
  • Short-term: Detailed analysis of strength and breadth of immune response following vaccination with high-dose (HD) versus standard dose (SD) influenza Fluzone vaccine.

Data

  • Open cohort of individuals who were vaccinated during the 2014/15 - 2018/19 flu seasons.
  • The default vaccine was the trivalent or quadrivalent standard dose (SD, 15µg) Fluzone vaccine.
  • Individuals >=65 were offered the high-dose (HD, 60µg) trivalent Fluzone vaccine.
  • Analysis of immune response (HAI) for SD vs. HD individuals.
  • Focus on individuals >=65 years, only look at B-strains that are in both SD and HD.

Study population

The data

The data

Outcome definition

Investigate 4 antibody titer (HAI) outcomes:

  • Titer increase following vaccination
  • Seroconversion, defined as pre-vaccination HAI titer <1:10 (LOD) and post-vaccination titer >= 1:40 OR a >=4-fold increase
  • Post-vaccination HAI titer
  • Seroprotection, defined as post-vaccination HAI >= 1:40

All HAI titer dilution values are converted (log-transformed) to a scale from 0 - N with Limit of Detection (LOD) = 0, lowest dilution (1:10) = 1, etc. up to highest dilution (1:20480) = 12.

Analyses

  • We implemented univariate, multivariate and propensity score matching models.
  • Each model was fit in a Bayesian framework.
  • Results show the difference in outcomes between HD and SD vaccine.

Strain-specicfic responses, H1N1

Median and 95% Credible Interval

Median and 95% Credible Interval

Multivariate model with age, gender, race, pre-vaccination titer.

Strain-specicfic responses, H3N2

Median and 95% Credible Interval

Median and 95% Credible Interval

Strain-specicfic responses, B

Median and 95% Credible Interval

Median and 95% Credible Interval

Heterologous responses, H1N1

Heterologous responses, H3N2

Heterologous responses, B

Vaccine-specific analysis

Same 4 outcomes as before, but now computed per vaccine/season:

  • For post-vaccination and increase in titer, the average response for all vaccine strains
  • For Seroprotection/Seroconversion, the fraction of strains that elicit a response

Vaccine-specific responses

Median and 95% Credible Interval

Median and 95% Credible Interval

Summary & Future

  • For most vaccine components, HD produces a stronger response against the vaccine strain and heterologous strains. However this is not fully consistent.
  • On a per-vaccine basis, HD is generally better at inducing a response.
  • Broader use of HD vaccine should be considered, further optimization of dose is likely possible.
  • Analyses using further variables as inputs or outcomes to start understanding mechanisms would be useful.

Thanks!