• Inoculum dose is an important determinant of infection or vaccination outcomes.
• For infection, higher dose is often associated with greater risk of infection (ID50) and more severe outcomes (LD50).
• For vaccines, dose is thought to impact both immunogenicity and side effects (morbidity).

Adenovirus type 5 (ADV) infections of cotton rats.

Li & Handel 2014 JTB

Infectious bronchitis virus (IBV) infections of chickens. (Coronavirus!)

Li & Handel 2014 JTB

Infected cells following influenza infection.

Moore et al 2020 BMB

Higher inoculum, higher virus load.

Moore et al 2020 BMB

Norovirus infections in humans at 3 doses.

• Generally, a few (~3) doses are explored in phase I and II trials.
• Based on those data, one of the doses is chosen in a non-rigorous manner.

Example of BioNTech/Pfizer COVID Vaccine

• Impact of dose on immunogenicity might not be monotone.
• Knowing in more detail how dose impacts immunogenicity and morbidity might help optimize dose choice.

Animals infected with flu (let’s pretend it’s a live/replicating vaccine).

Handel et al 2018 PLoS Comp Bio

Animals infected with HPIV (let’s pretend it’s a live/replicating vaccine).

Conceptual model suggests that protection (and morbidity) might be peaked (left flu, right HPIV).

See also: Rhodes et al 2016 Vaccine, Rhodes et al 2019 JTB

• Open cohort of individuals who were vaccinated (some repeatedly) 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 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.

Question: What is the impact of standard dose (SD) versus high dose (HD) vaccine on HAI?

Dropped H3N2-Singapore-2016 and B-Colorado-2017 due to small sample size.

Investigate 4 antibody titer (HAI) outcomes for each strain:

• Post-vaccination HAI titer
• Seroprotection, defined as post-vaccination HAI >= 1:40
• 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

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

Median and 95% Credible Interval

Multivariate Bayesian model, controlling for age, gender, race, pre-vaccination titer.

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

• For Seroprotection/Seroconversion sum of each strain, standardized (score from 0-1)
• For post-vaccination and increase in titer, the average for all vaccine strains

• Vaccine-specific heterologous response
• Other?

• HD vaccine seems to lead generally to more HAI against the vaccine strain, though it depends on strain and year. H3N2 seemed to benefit less from HD.
• There is a tendency for HD to induce better heterologous protection, but the effect is small and inconsistent.
• There might be interaction between dose and gender for some vaccine strains.
• This is an exploratory analysis, further investigation is needed.

• Dose is important, impact not that well studied.
• For a universal influenza (or coronavirus?) vaccine, strength and breadth of protection is important.
• Combination of data and models could help optimize vaccine dose choice.
• Getting the right kind of data is tricky.

• Collaborators:
  • Prior work: See published papers
  • Ongoing work: Mainly Yang Ge
  • CIVIC/CIVR-HPR members, especially Ye Shen, Ted Ross
• Funding: NIH
• Slides: https://www.andreashandel.com/talk/
• Contact: https://www.andreashandel.com/, @andreashandel

• What’s the best way to quantify overall response?
• How to deal with SD having 2 B-strains?
• Best scale for HAI titer analysis?
• Anyone know of accessible data sources for (flu) vaccination/infection at different doses?