The impact of seasonal influenza vaccine dose on homologous and heterologous immunity

Motivation

Current influenza vaccines are not that great.
Immunity following vaccination is especially low in older individuals.
An increase in dose (antigen) for the Fluzone vaccine has been shown to lead to somewhat better protection against the vaccine strains in older individuals.
It is unclear if the high dose (HD) vaccine leads to better protection against strains other than the vaccine strains.

Setup

Cohort of individuals who received Fluzone vaccine over multiple seasons.
Trivalent or quadrivalent standard dose (SD, 15µg) Fluzone vaccine was the default.
Individuals >=65 years were offered the high-dose (HD, 60µg) trivalent vaccine.
We evaluated immune response following vaccination, specifically antibodies as measured by hemagglutination inhibition assay (HAI).

Question: What is the impact of standard dose (SD) versus high dose (HD) vaccine on antibodies, especially against non-vaccine strains?

Study population

“Raw” data - homologous responses

“Raw” data - heterologous responses

Outcomes of interest

We investigate 4 antibody titer outcomes for each strain:

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

HAI values are converted to be between 0 - N, with limit of detection = 0, lowest dilution (1:10) = 1, up to highest dilution (1:20480) = 12.

Methods

Multilevel Bayesian mixed effects models. Mix of fixed and pooled/adaptive priors.

\(\begin{aligned} Y_{ij} & \sim \textrm{Normal}(\mu_{ij}, \sigma) \\ \mu_{ij} & = \alpha_{ID[i]} + \beta_{dose} DOSE_i \\ & + \beta_{age} AGE_i + \beta_{p} PHAI_{i,j} \\ & + \beta_{sex} SEX_i + \beta_{race} RACE_i \end{aligned}\)

Notation: i: individuals, j: strains.

Results - homologous response

Median and 89% equal-tailed credible interval

Heterologous H1N1 titer increase

Heterologous H1N1 seroconversion

Overall vaccine response - homologous

Overall vaccine response - heterologous

Research project summary

HD vaccine does overall provide better induction of immunity against vaccine strains.
HD is not always better for heterologous responses against non-vaccine strains.
There is noticeable variability between vaccine strains and seasons.

Some other projects

R packages to make modeling easier I

For teaching (stable):

R packages to make modeling easier II

For research (in progress):

Online modeling/analysis courses

Acknowledgements

Collaborators:
- Research project: Yang Ge, Amanda Skarlupta, Zane Billings, Ye Shen, Justin Bahl, Paul Thomas, Ted Ross
- Other projects: See each website
Funding:
- NIH