MICR5817 L8: Phase III Vaccine Trials 8/13/26

True or False: Vaccines have saved more lives than any other single medical advance

True

What are these?

-Polio in Paediatric ICU

-Neonatal tetanus

-Smallpox (most impactful in terms of reducing deaths)

-Diphtheria

-Cervical cancer

-Meningococcal ACWY & B disease

Diseases we no longer see in most developed countries

What vaccine was most impactful in terms of reducing deaths?

Smallpox

Name some diseases that we no longer see in most developed countries

-Polio in Paediatric ICU

-Neonatal tetanus

-Smallpox (most impactful in terms of reducing deaths)

-Diphtheria

-Cervical cancer

-Meningococcal ACWY & B disease

(Insert Image P5) List the steps of the Vaccine Cycle

1) Surveillance

2) Basic Research

3) Vaccine Development

4) Clinical Trials

5) Licensure of Vaccine

6) Policy and Implementation

What are some limitations of Animal Studies?

-Preclinical trials do not always predict results + efficacy in humans

-However, they are still important for testing potential new vaccines

(Insert Image P8) Describe the timing and processes for Drug/Vaccine Development

1) Preliminary stage (2-5y)

2) Nonclinical animal testing (1-2y)

3) Clinical Trial Phase I

4) Clinical Trial Phase II

5) Clinical Trial Phase III (Total: 4-8y)

6) Licensure (4-5y)

What is this?

-Safety/immunogenicity

-Dose finding

-20 to 100 healthy volunteers

-Manufacturing of clinical drug (small scaleup)

Phase I

What is this?

-Safety/immunogenicity

-Dose finding

-Several hundreds of healthy volunteers

-Commercial scaleup

Phase II

What is this?

-Thousands of healthy volunteers, test safety/immunogenicity

-Series of trials: Assess consistency of manufacturing, immunogenicity, etc

-Process validation -> large scale manufacture

Phase III

(Insert Image P9) Why is progression to Phase III not assured?

-FDA success rate for vaccines to progress from Phase 1 to Phase 3 is 44.5%

-FDA success rate from Ph1 to market approval is 33.4% (overall rate 14%)

(Insert Image P10) Describe the state of RSV vaccines/monoclonal antibodies

-Some monoclonal antibodies are also licensed for market

-Most new vaccines target older people instead of younger ones

Describe subjects in the target population for a Phase III Vaccine Trial

-Infants, children, older adults

-Pregnant mothers (recently, for RSV)

-Number is generally 3,000 to 10,000 individuals but can be much larger

How long and how much would a Phase III Vaccine Program cost?

-Length of trial: Generally 1 to 4 years

-Cost of trials varies but could be > $1 billion

List the 1st Aim of Phase III Vaccine Trials:

-Saves money on new efficacy study

Assess protective efficacy and crossprotective immunity using biomarkers

List the 2nd Aim of Phase III Vaccine Trials:

-Example: Person with antibody X is protected against Y

Identify laboratory correlates of protection if possible

List the 3rd Aim of Phase III Vaccine Trials:

-Pericarditis, myocarditis, clotting with Covid vaccine

Assess less common side effects and provide proof of safety

List the 4th Aim of Phase III Vaccine Trials:

-Administration with other vaccines (maybe separate studies)

Assess manufacturing consistency and batch to batch variation

What are these?

1) Evidence of safety and indications of potential success

2) Positive discussion with regulator(s) about study design

3) Sufficient funding to undertake study

4) Viable market (if successful)

5) Ability to successfully complete study

Requirements for Phase 3 Trials

Explain this requirement for undertaking Phase 3 trials:

1) Evidence of safety and indications of potential success

-Generally dependent on Phase 2B results or correlate of protection

-Example: Stopping carriage of organism in nose with pneumococcal vaccine

Explain this requirement for undertaking Phase 3 trials:

2) Positive discussion with regulator(s) about study design:

Determine appropriate endpoints, sufficient power, relevant population(s), and safety outcomes

Explain this requirement for undertaking Phase 3 trials:

3) Sufficient funding to undertake study

Needed for manufacturing product, study sites for conduct, monitoring, laboratory analyses

Explain this requirement for undertaking Phase 3 trials:

4) Viable market (if successful)

-Competitors, cost of good & scalability, therapeutic benefit, product demand, cost effectiveness

-Safety is not a major concern

-Support of key-opinion leaders

Explain this requirement for undertaking Phase 3 trials:

5) Ability to successfully complete study

-Sufficient interest from study sites and target populations

-Complexity of study

List all 5 requirements for undertaking Phase 3 trials:

1) Evidence of safety and indications of potential success

2) Positive discussion with regulator(s) about study design

3) Sufficient funding to undertake study

4) Viable market (if successful)

5) Ability to successfully complete study

How are Phase III studies designed?

-Double-blind or observer blinded randomised controlled trials

-Depends on availability + recommendations of current vaccines/disease epidemiology

-Need sensitive and specific laboratory and clinical diagnosis

What is an example of an ethics dilemma caused by the use of placebo vaccination vs a licensed comparator?

Influenza in the elderly

What is an example of a rare infection where it might not be feasible to conduct a study due to lack of sufficient cases?

Meningococcal disease

What is an appropriate comparator for testing the 30-valent pneumococcal vaccine?

Someone who gets the standard 20-valent vaccine

True or False: Viral Studies are almost always performed with PCR due to high sensitivity (except for Meningococcus)

True

What are these?

1) Absolute vaccine efficacy

2) Relative vaccine effectiveness

3) Comparative immunogenicity

Points assessed by Phase III Vaccine Trials

What is this Phase III Vaccine Trial measuring?

-Placebo-controlled trial with infection/disease endpoint

-RSV or COVID-19 trials

Absolute Vaccine Efficacy

What is this Phase III Vaccine Trial measuring?

-Compare the relative risk of infection in study vaccine vs comparator vaccine (e.g influenza)

Relative Vaccine Effectiveness

What is this Phase III Vaccine Trial measuring?

-Used for combination vaccines to demonstrate equivalence to separate licensed vaccines

-Example: Efficacy of pertussis combination vaccines

Comparative Immunogenicity

Name the most common design for novel vaccines where:

-No licensed comparators exist

-Correlates of protections are unknown for the population

Placebo Controlled Phase 3 Vaccine Trials

Describe how a Placebo-Controlled Phase III Vaccine Trial is organized

-Usually multi-centre, international trials at hospitals, trials centres and GPs

-Either use placebo or unrelated licensed vaccine (especially in children)

What does the sample size provide in a Phase III Vaccine Trial?

1) Efficacy Estimate

2) Confidence in detecting uncommon adverse events

What determines the duration of a Placebo-Controlled Phase III Vaccine Program?

-Number of events occurring that drive interim analysis + desired/expected efficacy

-Usually powered on lower bound (LB) of Confidence Interval

How are Placebo-Controlled Phase III Vaccine Trials usually powered?

-Lower bound (LB) of confidence interval

-COVID vaccines: LB 95% CI is more than > 30%

How do you calculate Absolute Vaccine Efficacy (VE)?

VE = (1 - Infection rate in vaccinated) / (Infection rates in placebo recipients)

What was the efficacy outcome of this Maternal RSV Vaccine Efficacy Study?

-Pfizer bivalent preF protein vaccine

-Recruited 7,300 healthy pregnant mothers

-Randomized 1:1 between ≥24 and ≤36 weeks gestation (when antibodies go back to general baseline)

Medically attended ALRTI for ~6 months

(Insert Image P16) Describe the Safety of the Maternal Bivalent RSV Vaccine:

-Local adverse events, systemic adverse events, adverse events of special interest in mothers and infants

-Erythema, swelling, pain

-No difference in systemic symptoms (fever is uncommon in pregnant moms)

-Slightly increases probability of early delivery and covid infection (not significant)

(Insert Image P17) Describe the efficacy of the Maternal RSV Vaccine against LRTI in infants

-Severe respiratory infections

-Vaccine efficacy highest in first 3 months

-Post 3 months: More breakthrough infections in babies

-Efficacy goes down, but 70% protected during 6 month period (less from 5-6 months of age)

True or False: Maternal Bivalent Pre-F Vaccine confers higher protection against RSV infection than MA-LRTI

True

(Insert Image P18) Describe the Maternal Bivalent Pre-F RSV vaccine efficacy

-Vaccine well-tolerated with no safety concerns for vaccinated mothers and their newborns

-Higher efficacy against severe disease and hospitalizations (higher in 3 months, maintained in 6 months, still effective up to 12 months)

What is this?

-Compares study vaccine to active licensed comparator vax

-Requires a high disease incidence + a licensed comparator with low efficacy against circulating disease

-Not feasible for many diseases

Relative Vaccine Efficacy Trials

What are the requirements for a Relative Vaccine Efficacy Trial to compare a study vaccine and an active licensed comparator vaccine?

1) High disease incidence

2) Licensed comparator vaccine with low efficacy against circulating disease

What is a disease that would be eligible for a Relative Vaccine Efficacy Trial due to high incidence rate + active comparator vaccines with low efficacy?

-Seasonal influenza vaccine in older adults

-Sample sizes are generally larger

-Can use cluster randomised control trials

What type of diseases might not be feasible to study in a Vaccine Efficacy Trial?

Diseases with severe outcomes such as hospitalization

(Insert Image P20) Describe the Relative Vaccine Efficacy of High Dose (HD) compared to Standard Dose (SD) influenza vaccines in older adults ≥65 years

-Relative efficacy of HD vaccine to SD TIV (Trivalent Inactivated Vaccine)

-Primary endpoint: 24% for lab-confirmed influenza

-Less adverse events in HD than SD group

What type of Phase III Trials is this?

-Disease incidence is too low for a placebo-controlled trial

-Uses standardized laboratory assays accepted by the regulators to that show the new vaccine is non-inferior

-Includes about 5,000 people from different populations

Comparative Immunogenicity Phase III Trial

List some reasons for why you would need to conduct a Comparative Immunogenicity Phase III Trial

1) Disease incidence is too low for placebo-controlled trial

2) Correlate of protection is known

3) Current vaccines are well established and are effective

What is the definition of Non-Inferioriy?

-Not measured by absolute GMC

-The lower bound of 2-sided 95% CI of rate of seroprotection or seroresponse is > -10%

-The lower bound of the 2-sided 95% CI for IgG GMC / GMT ratio to be >0.5

What are Comparative Immunogenicity Phase III Trials typically used for?

-Demonstrating consistency of batch-to-batch manufacturing in Phase III

-Testing combination and multivalent vaccines like PCV, PPV against Invasive Pneumococcal Disease

Give an example of each type of vaccine that would typically undergo a Comparative Immunogenicity Phase III Trial

1) Combination vaccines

2) Multivalent vaccines

1) Pertussis 6 in 1 vaccines

2) Pneumococcal + meningococcal conjugate vaccines

What determines the sample size of a Comparative Immunogenicity Phase III Trial?

-Sample size is more dependent on sufficient safety dossier

-Often have a number of similar studies in different populations submitted to regulators

Describe how Serum Bactericidal Antibody was used as a serologic correlate of protection from meningococcal disease in new army recruits

-Check case of hsBA to strain disease

-Each case is tested for SBA activity against actual strain-causing disease in matched case

-Same assay still used as the outcome in all meningococcal Phase III Trials

(Insert Image P22) Describe the Serotypes included in the Pneumococcal Conjugate Vaccine (PCV) and Polysaccharide Vaccine (PPV)

-In Australia, serotypes 22F and 33F account for 8 -10% of Invasive Pneumococcal Disease (IPD) cases in children < 2 years

-Serotype 3 is most common cause of PCV13 vaccine failure

(Insert Image P23) Describe PCV15 Trial Design for V114-029

-No differences in baseline demographics between groups (randomized)

-Compare PCV15 with licensed 13-valent vax

-PCV15 and PCV20 are now licensed for infants

Why is it necessary to measure Non-Inferiority of pneumococcal vaccines against Invasive Pneumoccocal Disease (IPD)?

-Compare how both vaccines protect against Serotype 3

-No less than 10 percentage points difference between response rates

-Serum protection is the most important

(Insert Image P24) Describe how IgG response rates and IgG GMC Ratio were used to assess non-inferiority

-Assess lower bound (LB) of the 2-sided 95% Cl for PCV15 and PCV13

-Difference in IgG Response Rates must be larger than > -10 percentage points

-IgG GMC ratio must be larger than >0.5

What was the outcome of the PCV15 Non-inferiority Assessment at 30 days post-dose 3?

PCV15 was non-inferior to PCV13 for all 13 shared serotypes based on the proportion of responders

(Insert Image P25) What are the implications of referencing subsequent multivalent vaccines to the initially listed vaccine?

-PCV13 is slightly less effective << original vaccine

-90% CI was still above 0.5 threshold

-PCV15 is probably also inferior to original vax

(Insert Image P25) Describe the theoretical impact of referencing subsequent multivalent vaccines to initially listed vaccine

-New vaccine (PCV15) protects 3x as many strains, but not as strongly immunogenic overall

-Possibility of vaccine failures

List some reasons that Phase III Trials may not achieve their objectives based on:

1) Disease Incidence Rate

2) Vaccination Timing

3) Inclusion/Exclusion Criteria

4) Trial Design

-Disease incidence is overestimated in trial population

-Timing of vaccination related to peak disease incidence

-Wrong population selected for trial

-Wrong trial design/endpoint selected

List some reasons that Phase III Trials may not achieve their objectives based on:

1) Trial protocol

2) Systematic data collection + trial endpoint

3) Lack of understanding about virus

-Trial is too complex for patients/sites

-Testing for trial endpoint fails to be systematic

-Example: Not swabbing for virus DNA properly

-Mechanism of protection is not understood, vaccine is ineffective

List some reasons that Phase III Trials may not achieve their objectives based on:

1) Safety

2) Duration of trial

3) Funding

-Safety issue identified

-Trial takes too long or competitor vaccine introduced

-Insufficient funding to complete trial, or vaccine is not cost-effective

(Insert Image P28) What is this?

-Operation Warp Speed

-US government invested $18 billion into pandemic vaccines

-Funded Pfizer-Biontech mRNA vax

-Total surveillance time: 1000 person-years for all subjects within each group at risk for the endpoint

(Insert Image P29) Describe the acceleration of Vaccine Development during COVID-19 pandemic through overlaps between Phase I-Phase III

-mRNA vax approved by FDA in 9 months

-Normally takes 5-10 years, start small scale manufacturing before commercial

-Commercial scale up to meet global demand, (billions of doses)

(Insert Image P31) Describe the vaccine efficacy of the Pfizer-Biontech mRNA vaccine

No reduction in efficacy with:

-Age

-Race/Ethnicity

-Country

-Underlying comorbidities

(Insert Image P32) Describe how different Covid-19 vaccines for Australia compare to each other

Pfizer/Biontech and Moderna can be stored at 2-8C for up to 30 days

What is the most critical part of a vaccine's success in being licensed?

Phase III Clinical Trials

Describe the preparation required for Phase III Clinical Trial

-Manufacturing, trial design patient population and funding

-All are critical to success

What factors influence variations in trial design?

-Availability of licensed comparator vaccines

-Disease incidence

-Complexity of the vaccine being studied

True or False: Multiple endpoints are important in Phase III Clinical Trials

True

What did the COVID19 pandemic demonstrate?

-Timelines for planning and successful conduct of Phase 3 trials can be significantly accelerated

-Requires sufficient funding and at-risk manufacturing of the vaccine