MICR5817 L7: Vaccine Trials Phase I and II 8/10/26

What is the underlying principle of Phase I-II Trials?

-Phase I/II vaccine trials are primarily designed to assess safety, dose, schedule and immune response

-Not to provide definitive proof of effectiveness

What do Phase I and II mean in vaccine trials?

-Phase I/II answers whether we have a plausible, safe and immunogenic candidate

-Justify larger-scale efficacy testing

-Same development ladder, slightly different emphasis from therapeutic drug trials

Describe some differences between Phase I, II and III Clinical Trials

-Phase I: Up to 100 participants, small molecule or biotherapeutic drug trial. Looking at safety

-Phase II: 200-400 participants, finding vaccine candidate, mostly healthy and some at-risk groups, trying to find patient groups

-Phase III: Have to invest 10s, 100s of millions of dollars, larger scale efficacy testing

Describe this stage:

-Phase I: First human safety tests and dose finding

-Emphasis on safety, tolerability, reactogenicity, dose selection and immune response

-Need to manufacture vaccine candidate to high standard so it is tolerable

-Additional testing for side effects in animals

What Clinical Data might be used uring Phase I?

-How they manufacture drug

-Determine if it will be effective, safe for humans based on animal testing

-In vitro -> in vivo -> humans

What should doctors know during Phase I Trials?

-Read investigator's brochure

-Know the starting dose and protocol

True or False: Vaccine Phase I studies may include more participants than small molecule Phase I trials

True

Why would Vaccine Phase I Trials require more participants than small molecule Phase I trials?

If multiple doses, schedules or adjuvant combinations are being compared

Describe this stage:

-Phase II: Expanded safety and immunogenicity

-Hundreds of participants are typically enrolled to further characterise safety, immunogenicity, dose + schedule.

-Want a plausible, safe + immunogenic candidate to justify larger-scale efficacy testing

True or False: Vaccine Phase II only test health volunteers, no at-risk populations are included

False

Why would Phase II Trials include at-risk groups in their eligbility criteria?

Prophylactic vaccines target prevention

What is the purpose of Pre-Clinical Studies?

-Help identify promising candidates, early safety risks and immune responses

-Many candidates that work in animals do not translate directly to humans

What do Pre-Clinical Studies assess?

1) Candidate Rationale

2) Pre-Clinical Evidence

3) Starting Dose

4) Trial Readiness

Identify this aspect being assessed in Pre-Clinical Studies:

-Target antigen and immune mechanism are selected.

Candidate Rationale

Identify this aspect being assessed in Pre-Clinical Studies:

-In vitro and in vivo studies assess safety and immune response

Pre-Clinical Evidence

Identify this aspect being assessed in Pre-Clinical Studies:

-Dose and route are justified before human exposure.

Starting Dose

Identify this aspect being assessed in Pre-Clinical Studies:

-Manufacturing, formulation, safety considerations etc. are established.

Trial Readiness

Describe this stage:

Phase I Vaccine Trial: Typical Design

-Randomised, blinded, placebo-controlled

-Required for redible early safety and immune-response data.

-May need adjuvant/drug company partnership

What type of vaccine study design is this?

-Participants are allocated to treatment arms by chance to reduce bias.

Randomized

What type of vaccine study design is this?

-Participant and blinded site staff remain unaware of allocation unless emergency unblinding is required

Double-blind

What type of vaccine study design is this?

-Includes saline or visually matched placebo to interpret adverse events and immune response.

Placebo Controlled

What type of vaccine study design is this?

-An adjuvant may enhance the body's immune response to the vaccine's antigen.

-Escalating antigen doses may be tested with and without adjuvant to justify progression.

Dose/Adjuvant Comparison

What would you expect a Phase I vaccine trial study design to include?

1) Randomized

2) Double-blind

3) Placebo-controlled

4) Dose/adjuvant Comparison

Describe this stage:

Phase I: Primary and Secondary Objectives

-Assess adverse events, vital signs, laboratory parameters and acute post-vaccination reactions across escalating dose/adjuvant groups

-Measure immune response by seroconversion and antibody titres to support dose and schedule decisions

What is this?

-Evidence that the vaccine candidate stimulates an immune response

Immunogenicity

True or False: Immunogenicity is the same as definitive clinical efficacy

False

What is the Primary Objective of Phase I Trials?

-Safety, tolerability, reactogenicity

-Assess adverse events, vital signs, laboratory parameters

-Find acute post-vaccination reactions across escalating dose/adjuvant groups

What is the Secondary Objective of Phase I Trials?

-Measure immune response by seroconversion and antibody titres

-Supports dose and schedule decisions (Phase II)

Describe this stage:

-Phase I Vaccine Trial: Study Schedule

-Practical view of what participants and site teams do across the visit window

-Schedule Assessments: All stuff you need to investigate

-Screened visits, take blood and urine for tests

True or False: During Phase I, screening and vaccination cannot occur on the same day

True

What is this?

-First group to be exposed to vaccine

-Check for acute response/adverse effects

-May need to stay 2-6 hours for observation

-Later groups may only stay 30 min to 1h instead

Sentinel Group

What would you expect to happen over the course of the Vaccine Trial Study Schedule?

1) Screening

2) Vaccination

3) Early Safety Followup

4) Final Safety Followup

5) Longterm Followup

What is this step in the Phase I Vaccine Trial Study Design?

1) Informed consent, eligibility checks and baseline assessments.

Screening

What is this step in the Phase I Vaccine Trial Study Design?

2) Pre-dose checks, intramuscular injection and acute observation

Vaccination

What is this step in the Phase I Vaccine Trial Study Design?

3) Diary review, symptoms, adverse events and safety labs.

Early Safety Followup

What is this step in the Phase I Vaccine Trial Study Design?

4) Safety window closure and ongoing AE review.

Final Safety Followup

What is this step in the Phase I Vaccine Trial Study Design?

5) Immunogenicity samples and selected safety monitoring

Longterm Followup

Describe this stage:

Participant Eligibility: Early Phase Vaccine Trials

-Eligibility criteria protect participants and reduce confounders in safety and immune-response interpretation

-Operational implication: Eligibility evolves as confidence grows

True or False: Phase II still protects data quality, but it should better approximate intended-use populations than Phase I

True

What populations would you expect during Phase II?

-Healthy adults in early phase and 18+

-May have trials on children or adolescents

-Subset in protocol of older participants (60+)

-Sometimes targeted (RSV for older people)

What are some considerations made during Phase II trials?

-Recent Vaccination: Might need to wait if less than 1 month, or if you just had a fever

-Tropical Diseases: Travel restrictions for next 6-12 months (studies on dengue/malaria)

-Avoid Pregnancy: Ask about contraception

True or False: Vaccine eligibility is more strict than other therapeutics

True

List some Common Inclusion Features

-Healthy adults, 18+

-Upper age cut-off or older-adult subgroup depending on protocol

-Ability to comply with visits, diaries + followup

List some Typical Exclusions

-Pregnant or breastfeeding

-Recent vaccination or active febrile illness

-Relevant travel restrictions

-Medical history that may affect safety interpretation

Describe this stage:

-The Vaccine Candidate: Preparation and Blinding

-Product presentation drives pharmacy, nursing and safety-review workflows

-Pretty early in development

-Unblinded team for preparation/dispensing

True or False: Unblinded teams cannot be the same nurses treating the patients, as they might make assumptions based on what the subject received

True

Describe the vaccine dosage during the Early Phase I

-Multiple active dose strengths

-Adjuvant and non-adjuvant arms

-Placebo, often saline or visually matched

-Frozen or ultra-cold storage may be required due to limited stability data

Describe the Blinded/Unblinded Split in Phase I Trials

-Unblinded team may prepare, randomise and administer

-Blinded safety team remains separated from product preparation where required

-Emergency unblinding process is protocol controlled

How are sites selected for Phase I vaccine trials?

-Dedicated early phase units are designed to manage intensity, control and safety oversight

-Operational control is part of risk-management strategy

True or False: Site selection for clinical trials is only based on ability to recruit

False

What are some considerations that should be made when selecting sites and running Phase I Vaccine Trials?

1) Safety Readingess

2) Specialist Facilities

3) Blinded Operations

4) Recruitment Capability

What aspect of site selection and preparation for running Phase I Clinical Trials is this?

-Medical cover, emergency response and acute reaction management

Safety Readiness

What aspect of site selection and preparation for running Phase I Clinical Trials is this?

-Pharmacy, laboratory processing, centrifuges and cold-chain storage

Specialist Facilities

What aspect of site selection and preparation for running Phase I Clinical Trials is this?

-Clear separation between product preparation and safety assessment

Blinded Operations

What aspect of site selection and preparation for running Phase I Clinical Trials is this?

-Healthy volunteer recruitment, screening capacity and visit compliance.

Recruitment Capability

What is this Phase I Vaccine Trial?

-Tetravalent formulation, adjuvant with 3-dose schedule

-Must be -80C, sponsor wants to outsource storage

-Pretend to get placebo out of freezer to maintain the blind

Dengue Vaccine V180

Describe the Study Profile of Dengue Vaccine V180 (Phase I)

Study: V180-001

Sponsor: Merck Sharp & Dohme LLC

Status: Completed

Phase: Phase 1

Actual enrolment: 98 healthy adults

Describe the Design Features of Dengue Vaccine V180 (Phase I)

-Randomised, double-blind, placebo controlled dose-escalation trial

-Tetravalent recombinant subunit formulations

-Compared adjuvanted/unadjuvanted formulations with placebo

-3 dose approach (Month 0, 1 and 2)

Describe the Operational Teaching Point of Dengue Vaccine V180 (Phase I)

-Multiple dose/adjuvant combinations increase pharmacy complexity, blinding requirements and scheduling discipline.

-Storage requirements created site-specific workarounds.

What is this Phase I Vaccine Trial?

-3 to 4 yr development reduced to

SCB-2019 Vaccine

True or False: In order to make SCB-2019 within a 12 month period, sequencing was done by removing core early phase questions

False

True or False: COVID-19 compressed development of SCB-2019 while still preserving safety and immunogenicity endpoints

True

Describe the Study Profile of Covid Vaccine SCB-2019 (Phase I)

Study: CLO-SCB-2019-001

Sponsor: Clover Biopharmaceuticals AUS Pty

Status: Completed

Phase: Phase 1

Actual enrolment: 166

Describe the Design Features of Covid Vaccine SCB-2019 (Phase I)

-Randomised, double-blind, placebo controlled first-in-human study

-Assessed SCB-2019 at multiple dose levels

-Two IM injections with and without adjuvant

-2 dose approach (Day 1 and 22)

Describe the Teaching Point of Covid Vaccine SCB-2019 (Phase I)

-Concurrent adult and older-adult cohorts and adjuvant comparisons

-Expedited approval pathway with rolling review of pre-clinical data

-3-4 year period reduced to

Describe this stage:

-Phase II Vaccine Trials: Study Design

-Sponsors make larger investment, expand program

-200-400 participants

-Can merge Phase I protocol into Phase II

What is this?

-Phase IIb (2B)

-Up to 1000 participants

-Merges Phase I protocol into Phase II

What questions are asked during Phase I and Phase II?

-Phase I: "Can we proceed?"

-Phase II: "Which formulation, dose and population should go forward?"

True or False: In Phase II, monitoring is reduced in frequency/intensity, but there is still followup for a year or two

True

What considerations should be included in Phase II Vaccine Trial Study Design?

1) Scale and Structure

2) Optimization Focus

3) Safety Model

What is this aspect of Phase II Vaccine Trial Study Design?

-Hundreds of participants are typical, with some Phase 2B studies approaching Phase III scale

-Phase I/II protocols may continue seamlessly once sentinel safety conditions are met

Scale and Structure

What is this aspect of Phase II Vaccine Trial Study Design?

-Dose, schedule, adjuvant and formulation are refined

-Placebo control often remains important for safety and immunogenicity interpretation

Optimization Focus

What is this aspect of Phase II Vaccine Trial Study Design?

-Monitoring may reduce in intensity once prior dose levels and adjuvants have been adequately assessed

-Longterm followup remains common for immune response sampling

Safety Model

Describe this stage:

-Phase II Objectives: Choose the candidate to take forward

-Objective: Not only to show a signal, also make a development decision.

-Good early data should narrow uncertainty

-Is it a strong immunogenic response? Do we need a booster?

True or False: Phase II is a selection gate (for the correct vaccine preparation and level of immunogenicity)

True

What is Decision Question 1 of Phase II?

Which vaccine preparation, dose and schedule has the best balance of safety, tolerability and immune response?

What is Decision Question 2 of Phase II?

Is the immune response strong, durable and interpretable enough to justify a larger confirmatory Phase III program?

Describe this stage:

-Phase II Eligibility: Expanding toward intended-use populations

-Population broadens as safety confidence increases

-Move away from healthy younger adult population (includes children)

-Control eligibility to interpret safety/immunogenicity clearly

True or False: For a Phase II trial, a 12 yr old cannot sign their own consent but can assent (show that they understand info)

True

How is Phase II recruitment/eligibility criteria different from Phase I?

-Older adults + participants with stable comorbidities

-Children, adolescents or pregnant women

-Minors assent processes + parent/guardian consent.

Under what conditions would you include this group in your Phase II trial?

-Older adults and participants with stable comorbidities

Include if relevant to the target population

Under what conditions would you include this group in your Phase II trial?

-Children, adolescents or pregnant women

May be considered only with appropriate prior data, ethics and regulatory support

Is this Phase I or Phase II?

-Protects the participant and the signal

Phase I

Is this Phase I or Phase II?

-Starts asking whether the signal holds in a population closer to real-world use

Phase II

Describe this stage:

Phase II Operations: Product and Site Model

-Operational Intensity and Dosage Options decreases

-Scale and Coordination increase.

-CRO coordination is bigger: managing multiple sites and larger enrolment

What are some aspects of Phase II Operations?

1) Product Presentation

2) Site Network

Describe this aspect of Phase II Operations:

-Product Presentation

-Reduced dose/adjuvant options

-More stability data

-More likely refrigerated storage

-Blinded pre-filled syringes or web-based kit allocation

Describe this aspect of Phase II Operations:

-Site Network

-Dedicated Phase I site may continue if Phase II follows Phase I/II protocol

-More sites often added to meet enrolment targets

-CRO coordination becomes more prominent

What is changed between Phase I and Phase II?

-Less acute observation than during Phase I

-More attention on recruitment, retention, protocol consistency and sample logistics across sites

Describe this stage:

-Early Effectiveness: Immunogenicity, efficacy and challenge models

-Immune response is not the same as disease prevention

-Challenge Study: Put participants in isolation rooms post-vaccination, expose to pathogen (CHIM)

What are some measures of Early Effectiveness?

1) Immunogenicity

2) Efficacy

3) Human Challenge

What is this aspect of Early Effectiveness?

-Measures the type, magnitude and durability of immune response

-Common outputs include seroconversion, antibody titres and neutralising antibody measures

Immunogenicity

What is this aspect of Early Effectiveness?

-Disease prevention is assessed by comparing vaccine and placebo groups for clinical outcomes such as symptomatic cases, hospitalisations or deaths

-Definitive proof is usually Phase III

Efficacy

What is this aspect of Early Effectiveness?

-Selected Phase II challenge studies can provide early protective efficacy insights

-Performed under carefully controlled conditions

-Require specialized isolation, safety and governance arrangements

Human Challenge

How did COVID-19 change the landscape of Phase I-II vaccine clinical trials?

-Showed that phases can overlap and manufacturing can begin at financial risk

-Corners were not cut

-Instead, overlapped timelines for data collection to speed it up

What previously impossible protocol changes did the Phase I-II vaccine clinical trials for Covid-19 demonstrate?

-Phases can overlap

-Manufacturing can begin at financial risk

-Core endpoints still remain intact

Where did the acceleration during the Covid-19 vaccine trials come from?

-Parallelisation, platform knowledge, funding and regulatory pragmatism

-NOT from skipping core safety questions

Describe CEPI's 100 Days Mission

-Aims for safe, effective and accessible vaccines

-Within 100 days of identifying a new pandemic threat

What did CEPI emphasize with the 100 Day Mission?

-Cross-sector Health-Defense Collaboration

-Platform Technologies, Rapid Design Tool

-Manufacturing and Equitable Access