Infectious disease emergencies are opportunities to test the efficacy of newly developed interventions (e.g. drugs, vaccines and treatment regimens), yet they raise many intertwined challenges of politics, logistics, ethics, and study design. Consistent with the efforts of CEPI, WHO, and others to encourage development and Phase I/II testing of candidate vaccines (the focus of this talk) in advance of emergencies, it is essential before the emergency strikes to advance the discussion of how such products can and should be tested. This can help to disentangle ethical from political and logistical concerns, reduce the time pressure to make a decision, and encourage rational deliberation by future stakeholders who at the time of deliberation do not know what role (which product, which field site) they may be supporting in an actual emergency. At this luncheon, Professor Marc Lipsitch described his work on computer simulation of vaccine trials during epidemics to assess options for trial design, as well as some of his recent work on the ethics of trials in emergencies, with the aim to stimulate discussion on the intersection of these two topics. For more, please see our website: http://petrieflom.law.harvard.edu/events/details/digital-health-harvard-series-november-2018

1. Funded by the National Institutes of Health
Computer Simulations to
Enhance Vaccine Trials
Marc Lipsitch
Digital Health @ Harvard
November 27, 2018

2. Providing safe, effective vaccines to those who need
them, fast
Basic research
Candidate
Vaccine(s)
Animal
Testing
Safety/Immunog
enicity Trials
Efficacy/Effect
iveness Trials
Licensure &
Deployment

3. Basic research
Candidate
Vaccine(s)
Animal
Testing
Safety/Immunog
enicity Trials
Efficacy/Effect
iveness Trials
Licensure &
Deployment
Ebola 2014
Many potential threats

4. Coalition for Epidemic Preparedness
Innovations (CEPI)
$1 bn fund from foundations, governments established 2016
to:
• Move candidate vaccines against anticipated threats
through human safety and immunogenicity testing
• Establish platform tech to rapidly produce vaccines against
unanticipated threats

5. Basic research
Candidate
Vaccine(s)
Animal
Testing
Safety/Immunog
enicity Trials
Efficacy/Effect
iveness Trials
Licensure &
Deployment
Many potential threats

6. Ebola 2014-5 in Guinea, Liberia, Sierra
Leone
• Near-exponential growth
• Urgency to identify countermeasures
• to mitigate an accelerating epidemic
• Incidence spatially patchy
• Low, declining case
numbers
• Incidence becoming even
more patchy in space
• Urgency to test
countermeasures before
cases become too rare to
conduct trial

7. Agenda
• Develop new trial approaches and understand properties of existing
ones as they would be implemented in emergencies
• Develop ethical understandings of the special issues raised by trials
in emergencies
• Compile current understandings into “playbook” – dynamic and
updatable

8. Power is not the only question in trials
• BIAS: Often trials seek to estimate something other than the
individual-level protective effect of the vaccine.Will they do so
accurately?
• FEASIBILITY: If a trial is implemented, given logistical
constraints, can it work?
• What must happen how well/fast to make it work?
• ETHICS: how does trial affect risk for various group inside and
outside the trial?

9. Example 1: Ring vaccination trial
• WHO-led trial of rVSV EBOV
vaccine in Guinea was first trial of
this strategy
• Comparing immediate
vaccination of contacts of a case,
vs. 3-week delayed vaccination of
contacts
http://www2.cedarcrest.edu/academic/bio/hale/bioT_EID/lectures/sm
allpox-mass-ring-vac.html Henao-Restrepo et al. Lancet 2015;
Ebola ca suffit Consortium BMJ 2015

10. Success of Guinea trial suggests this could be a
valuable model for future trials in emergencies
Our goal: to model the determinants of feasibility, power, and possible biases
for future trials using this design

12. Disease dynamics in the study
population
• Small, homogeneous population (ring) using an SEIR stochastic
compartmental model
• Active follow-up of study population occurs and identified individuals are
hospitalized (H compartment), ending infectiousness
• Vaccination of susceptible individuals (to compartment SV) reduces per-
exposure probability of transmission
• Exploring a wide range of parameter values beyond those actually
occurring in the Ebola trial

13. Stochastic disease dynamics within each
ring
S
E I
H
R
βI
rE
rD
rISV βVI
vaccination
(deterministic at
fixed time)

14. Simulated trial design
• Case seeded in a small group (potential ring)
• Following index case identification, contacts (a “ring”) are
randomized to vaccination immediately or after a delay and
followed for disease
• Only cases detected in a pre-specified time window of
etiologic relevance are counted in the trial
• Therefore more efficient case detection increases the
number of events observed but decreases transmission in
the ring

15. Model outputs
•Estimated incidence rate in all rings is used to
calculate necessary sample size for a desired power
•100 trials are performed at this sample size to
estimate the vaccine effectiveness (VE) that would
be observed in such a trial

16. Incidence during
trial

17. Individual-level efficacy
Attenuated - misclassification
Slight upward ”bias” –
capturing indirect effects

18. Daily detection probability
More efficient trial conduct = larger sample size!!
Efficient case detection reduces transmission
and thus indirect effects, reducing effect
estimate

19. Infections from outside the ring
Indirect effects of vaccine are smaller if the
infections mainly come from outside the ring Yet sample size decreases slightly with more
external infections, because the trial is less
disruptive to the infection process

20. Baseline attack rate

21. Administrative delay

22. Start day of window

23. Key findings
• Sample size andVE estimate sensitive to:
• Intensity of case detection and administrative delay between index case
identification and ring vaccination
• Time window of case-counting
• Proportion of infections from outside the ring and attack rate in the controls
• Properties of the vaccine: pre- and post-exposure efficacy
• The effect of these parameters is either to reduce the incidence rate
difference between the arms, or reduce incidence rate in both arms

24. Conclusions: Ring vaccination cluster-
randomized trial
•Design can work with disease with well-
characterized natural history near end of epidemic
•Quantity measured is a composite of direct and
indirect effectiveness, pace publications calling it
“efficacy”
•Efficient case detection a double-edged sword

25. Example 2: Efficacy against
asymptomatic infection
Rebecca Kahn (now PhD student)
Matt Hitchings (recently completed ScD)
Steve Bellan (UGA)
RuiWang (HMS/HSPH)
American Journal of Epidemiology 2018

26. Asymptomatic infections: Who cares?
• Zika, Nipah and Lassa are all infections on the lists of CEPI orWHO with a high
proportion asymptomatic among all exposed persons
• (some evidence Ebola and others too)
• Persons without acute symptoms can
• Transmit to sex partners, fetuses, mosquitoes, others
• Have sequelae (eg Guillain Barre for Zika)
• So would like to measure efficacy against asymptomatic infection
• Standard time-to-event analysis using symptomatic cases underestimates
efficacy if it’s positive
• Susceptibles are removed faster than we observe, depleting the susceptible population
faster than we think
• More so for controls than intervention group
• Apparent incidence in controls is underestimated more than in intervention group
• Disproportionately low incidence in controls = bias to null.

27. Differential misclassification of at risk person-time
Vaccine
Control
Infected

28. Differential misclassification of at risk person-time
Vaccine
Control
Symptoms
Vaccine
Control
Infected
At risk

29. Differential misclassification of at risk person-time
Vaccine
Control
Symptoms
Perceived at risk
Vaccine
Control
Infected
At risk
• Susceptibles are removed faster than we observe - more so for controls
• Apparent incidence in controls is underestimated more than in vaccine group  bias
towards the null

30. Ideal: test people with serology every
week to detect asymptomatic infections
• Expensive
• Serology nonspecific esp for Zika
• Can we test people once or a few times, and can we test only in some
communities where we think we’ll learn the most?

31. • Goal: To test if estimating vaccine efficacy against all infection (not
just symptomatic infection) in a subset of communities is
representative of vaccine efficacy for the entire trial
• We identify the sample of communities by sampling a random 10%
of communities
• Impute the asymptomatic infections in all communities using
symptomatic ratio from these communities
Imputation

32. Simulations
• Results are shown from simulations for the following parameters:
• Ro (for communities): 1, 1.25, 1.5
• Note: Ro in source population is >1
• Trial length: 150 days
• % of population enrolled in trial: 7.5%
• Proportion symptomatic:
• Vaccine & control groups: 20%
• Vaccine: 10%; control: 20%
• Results are shown for the entire trial (all communities) and the sample of
10% communities
• Note: medians are shown
• Direct vaccine efficacy set to 0.60 against all infections; no effect on
probability of symptoms given infection

33. 1. Cox “Perfect Knowledge”
2. Cox: Symptomatic Only
3. Relative Risk Estimate
4. Corrected Relative Risk Estimate
5. Interval Censored (3 intervals)
6. Interval Censored Cox Model (1
interval)
7. Imputation
Accurate estimates with limited resources

34. Connections to research ethics
• Are randomized trials needed in emergencies?
• Are they ethical (including with placebo)?
• Can they be optimized to maximize public
health benefit in case vaccine proves effective
(Harling, Wang, De Gruttola, Onnela)?

35. Are there circumstances where we would
forego randomized efficacy trials because
rolling out a vaccine is so urgent?
• Strong presumption in favor of requiring efficacy RCT before rollout
• Economic
• Regulatory
• Ethical
• Historic: Examples of promising vaccines that actually did harm upon exposure
• But perhaps some scenarios so dire that rollout while observing could be
desirable
• Which conditions, and how?
• Best observational designs (or a combination) to estimate safety and efficacy

36. New project: Incorporating pathogen
sequence data into vaccine trials to
estimate who infected whom and thereby
enhance inference of vaccine effects

37. Conclusions: Emergency trials
• Simulations can aid in trial design for infectious diseases
• Pre-emergency study of properties of novel designs can help speed
trials in emergencies
• Ethics are entangled with methodology – should discuss and try to
settle both during peacetime
• Ring vaccination a promising trial design for end of epidemic but with
some caveats
• Asymptomatic infection efficacy can be studied in a standard trial
with one serologic survey at end in a subset of communities

38. Example 3: S. pneumoniae (pneumococcus)
vaccine
• Transmitted mainly between healthy carriers
• Meningitis, bacteremia, pneumonia, otitis: 3.7m severe episodes
• 295-515,000 annual deaths under 5 estimated for 2015
• 92+ serotypes, capsular polysaccharide: differ in many characteristics
• 13-valent capsule-conjugate vaccine PCV13 (previously, PCV7)
-Highly effective vs. targeted types: 16% reduction in mortality in Gambia
-Serotype replacement
-Expensive
Wahl et al. Lancet 2018

39. Vaccines
• Pneumococcal conjugate
vaccines exist
• Limited coverage of serotypes
(esp in developing world)
• Serotype replacement
• Expensive
• Alternative: Killed whole-cell
vaccine

40. Mechanism of WCV action: faster
clearance
Y Lu, et al. PLoS Pathogens 2008This immunity is antibody-independent,
dependent on CD4+ Th17 cells

41. Prevalence endpoint
Nonlinear relationship
between endpoint and
efficacy when efficacy is on
acquisition or duration
H Rinta-Kokko et al. Vaccine 2009

42. Multiple simultaneous processes
Birth infant toddler
Acquired immunity: duration of carriage
Cumulative exposure to colonization
Acquired immunity: acquisition probability

43. Modeling pneumococcal transmission
• Individual-based model
• Host demography, acquisition and loss of colonization
• Arbitrary number of serotypes could be carried at once
• Serotype-specific immunity against reacquisition
• Serotype-transcending immunity reduces duration
• Fitted to data kindly provided by Anthony Scott on serotype-specific carriage in
Kenya
• Age-specific transmission matrix from Kiti et al. 2014 PLoS One for Kilifi
• Incorporated vaccine effect on duration
Cobey & Lipsitch Science 2012

44. Simulating an individually-randomized trial
actual design
General Population
V C
simulation

45. Results
F Cai et al PLoS Comp Bio 2018

46. Design/Efficiency Questions
•Should trial study infants or toddlers?
(ConventionalWisdom: the group with the highest
incidence, toddlers)
•Is trial most efficient in high-incidence setting?
(Kenya vs hypothetical reduced-incidence)
(CW: yes)
•When should sampling occur?
(CW: soon after vaccination)

47. Infants more efficient: less natural immunity,
lower prevalence so less saturation

48. Lower transmission setting more efficient
Lower Kenya

49. Delayed measurement more efficient
Lower Kenya

50. Pneumococcal vaccine trial conclusions
•High-incidence settings not always most powerful
•Infants > toddlers for this vaccine
•Sampling ideally 9+ months post vaccination
•Kenyan toddler immunogenicity study had been
badly underpowered for efficacy
•Can design more efficient trials for efficacy

51. Collaborators
Ring vaccination trial
(Funding: NIH/NIGMS/MIDAS)
Matt Hitchings
Steve Bellan
Ongoing work
Rui Wang
Rebecca Kahn
Victor DeGruttola
Lee Kennedy-Shaffer
Sarah Lapidus
Pneumococcal vaccine trial
(Funding: PATH Vaccine Solutions)
Francisco Cai
Sarah Cobey
Thomas Fussell
Ethics
Annette Rid
Rebecca Kahn
Nir Eyal

53. Methodology
Network
• Generate a network of individuals grouped into communities
• A connection between two people represents a daily contact
between them, meaning all susceptible individuals have a daily
probability of infection from each of their infectious neighbors of
1-e-β ,where ß is the force of infection.
• Every individual is connected to a larger source population.
Epidemic
• Simulate a seasonal deterministic epidemic in source population
and stochastic epidemic in communities
• Disease follows Susceptible-Exposed-Infectious/Symptomatic (or
Infectious/Asymptomatic)-Recovered (SEIS(IAS)R) model
Vaccine Trial
• Enroll people in trial and individually randomize to vaccine or
control
• Vaccine is leaky (reduces probability of infection upon each
exposure)
• Goal: estimate vaccine efficacy against all infection (not just
symptomatic infection)
• Want to estimate accurately in most efficient way possible,
so we try 6 different methods

54. Analysis: Methods for Estimating Vaccine Efficacy (in full trial and
sample)
• Cox Perfect Knowledge
• A Cox proportional hazards model assuming exact day of infection is known for all cases, regardless of
status.
• Cox Model Symptomatic Only
• A Cox proportional hazards model for only symptomatic infections. This method assumes exact day of
known for all symptomatic cases, while all asymptomatic cases are treated as non-events and censored at
the trial.
• Interval Censored Cox Model (3x) or 1x
• An interval censored Cox model with the exact day of infection known for the symptomatic individuals and
ranging from the day of the most recent negative serologic test to the day of a positive serologic test for
asymptomatically infected individuals (serologic testing conducted at end of trial +- twice during
• Use icenReg package ic_sp (semiparametric)
• Relative Risk Estimate
• 1 −
𝐴𝑡𝑡𝑎𝑐𝑘 𝑅𝑎𝑡𝑒 (𝑉𝑎𝑐𝑐𝑖𝑛𝑎𝑡𝑒𝑑)
𝐴𝑡𝑡𝑎𝑐𝑘 𝑅𝑎𝑡𝑒 (𝐶𝑜𝑛𝑡𝑟𝑜𝑙)
• Corrected Relative Risk Estimate
• 1 −
𝑙𝑛 ( 1−𝐴𝑡𝑡𝑎𝑐𝑘 𝑅𝑎𝑡𝑒 (𝑉𝑎𝑐𝑐𝑖𝑛𝑎𝑡𝑒𝑑))
𝑙𝑛(1−𝐴𝑡𝑡𝑎𝑐𝑘 𝑅𝑎𝑡𝑒 (𝐶𝑜𝑛𝑡𝑟𝑜𝑙))