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The study materials/presentations are solely meant for academic purposes

and they can be reused, reproduced, modified, and distributed by others for
academic purposes only with proper acknowledgements.
BTE 722 Vaccine technology
History of vaccine development- Importance of vaccines . Immunological response to vaccines
Vaccine safety-the debate.

Different types of vaccines: Inactivated toxins, Inactivated whole bacteria or viruses, Live
attenuated bacteria or viruses; Subunit vaccines, Polysaccharide vaccines, Conjugated vaccines ;
Recombinant DNA vaccines, Edible vaccines, Virus like particles; Next-generation vaccines:
Human Immunome project; Human antibodies as vaccines.

Vaccine design and development: Epitope identification; Vaccine efficacy, Adjuvants ; Delivery
methods: microspheres, nanoparticles; ISCOMS and immunomodulators.

Production techniques used for vaccines ; Storage and preservation of vaccines.

Regulatory issues in vaccine production: OIE guidelines for production and seed lot
management; Manufacturing recommendation; Final product release tests.
Steps in vaccine production
• Exploratory: This research-intensive phase of the vaccine development process is designed
to identify “natural or synthetic antigens that might help prevent or treat a disease.”  

• Pre-clinical: During this phase, researchers — usually in private industry — use tissue-


culture or cell-culture systems and animal testing to determine whether the candidate
vaccine will produce immunity. Many candidate vaccines don’t move on to the next stage of
development because they fail to produce that immunity or prove harmful to test subjects.

• Clinical development: At this point, a sponsor, usually a private company, submits an


application for an Investigational New Drug (IND) to the U.S. Food and Drug Administration
(FDA). This summarizes findings to date and describes how the drug will be tested and
created. An institution that will host the clinical trial holds a review board for approval of
the application. The FDA has 30 days to approve the application. Once the proposal has
been approved, the vaccine must pass three trial stages of human testing:
• Phase I administers the candidate vaccine to a small group (less than 100 people) with the
goal of determining whether the candidate vaccine is safe and to learn more about the
responses it provokes among test subjects.
• Phase II, which includes hundreds of human test subjects, aims to deliver more
information about safety, immunogenicity, immunization schedule and dose size.
• Phase III, which can include thousands or tens of thousands of test subjects, continues
to measure the safety (rare side effects sometimes don’t appear in smaller groups) and
effectiveness of the candidate vaccine.

• Regulatory review and approval: If a vaccine passes through all three phases of clinical
development, the vaccine developer submits a Biologics License Application (BLA) to
the FDA.

• Manufacturing: Major drug manufacturers provide the infrastructure, personnel and


equipment necessary to create mass quantities of vaccines. They also reap the profits
of successful or widely distributed drugs.

• Quality control: The approval and distribution is far from the end of the line.
Stakeholders must adhere to procedures that allow them to track whether a vaccine is
performing as anticipated. Multiple systems — including Phase IV trials (optional
studies that can be conducted following the release of a vaccine), the Vaccine Adverse
Event Reporting System (VAERS) and the Vaccine Safety Datalink — are designed to
monitor the performance, safety and effectiveness of an approved vaccine.
Phase I trial
• Refer to the first administration of a vaccine candidate to humans. The primary
objective is to evaluate the safety and reactogenicity, while the secondary objective is
collection of immune response. Often times, the dose, immunization schedule and
mode of vaccine administration are also assessed.

• First-in-man Phase I studies are usually small trials in healthy, immunocompetent


naïve adults who are at low risk of acquiring a vaccine-relevant infection (determined
by serology, exposure, and travel history).

• Based on results of adult studies (referred to as Phase Ia trials), subsequent Phase I


studies may be conducted in different age or population groups closer to the target
population to assess possible differences in dose, safety, vaccine schedule, or route of
administration. Such subsequent studies in different geographies and populations are
referred to as Phase Ib

• Phase I trials are usually open-label and nonrandomized, but it is possible to conduct
randomized controlled trials (RCTs) in which a placebo or a vaccine against a different
disease is used as a comparator.
Phase II trial
• A candidate vaccine should proceed to Phase II clinical evaluation after
achieving a satisfactory outcome in Phase I studies in terms of both safety and
immunogenicity

• The objective is to identify the vaccine preparation, optimal dose, and schedule
to be taken up for confirmatory Phase III trials.

• These studies have the desired statistical power and a defined sample size, and
hence are expected to provide a clinically meaningful outcome on the safety,
immunogenicity, and efficacy end points.
Phase III Vaccine Trials

• Larger trials, involving thousands to tens of thousands of people. These Phase III
tests are randomized and double blind and involve the experimental vaccine
being tested against a placebo.

• Phase III goal is to assess vaccine safety in a large group of people.

• Vaccine efficacy is tested as well. These factors might include 1) Does the
candidate vaccine prevent disease? 2) Does it prevent infection with the
pathogen? 3) Does it lead to production of antibodies or other types of immune
responses related to the pathogen?
Vaccine clinical trials

The demonstration of vaccine efficacy (VE), typically through a Phase 3 trial, is fundamental
for licensure
ITT versus PP
Endpoints of trial:

Durability; time frame ; boostering


Immunological response
Safety

Non-inferiority trials ?
REGULATION OF VACCINES :

Regulatory issues related to a particular candidate vaccine should be


considered early in the development process, since regulatory compliance is
the basis for eventual approval.

It is strongly recommended that dialogue be established early on with the


appropriate National Regulatory Agency which should review developmental
plans for the candidate vaccine and clarify requirements for carrying out
clinical trials, as well as for marketing approval.

The regulation of vaccines can be divided into three stages: developmental,


licensure and post licensure. The developmental stage consists of two parts,
preclinical research and development, and clinical research and development.
The following differences from drug development mandates special precautions while
conducting vaccine clinical trials in a population:

I. Unlike drugs, which are given to patients, vaccines are received by healthy
individuals, thus the safety margin should be very high.
II. Vaccines have to be stored under refrigeration, there are always logistical challenges
during clinical trials considering that Phase II and Phase III are field studies.
III. The trial design gets complicated due to the possibility of interference during
coimmunization.

Note : The clinical development for vaccines for infants involves a step-down approach
where safety is first tested in adults, followed by adolescents, children, and lastly
infants.
Regulatory authorities
National regulatory authorities
Emerging global market leads to an increased the volume of biological medicinal products crossing national borders continues to rise, and it has become critical that regulatory knowledge and experience concerning them can be shared, and approaches to their control harmonized to the
greatest extent possible

Through its consultative approach, WHO identifies and consolidates current consensus opinions on key regulatory issues, and communicates them to national authorities and manufacturers through guidance documents addressing both general issues and specific products.

Through this mechanism, national regulatory authorities are informed on the scientific background needed to assess critical issues, and are advised on which regulatory approaches and methodologies have been found to be optimal for insuring the global supply of uniformly high, quality,
and efficacious biological medicinal products.
Addressing new challenges: development of innovative
regulatory pathways for novel vaccines

The NRAs of these countries need to rapidly be able to:


• establish regulatory strategies to regulate clinical trials taking place in their
countries
• perform a regulatory review of clinical trial applications
• assess clinical data and product characteristics to respond to license
application.
Regulatory pathways initiative:
The regulatory pathways initiative aims at addressing the challenges faced by
developing countries that are target for clinical trials or introduction of new
vaccines.

The objectives are:


• the support for the preparation and implementation of regulatory strategies
for the assessment of clinical trial applications
• The establishment of regulatory mechanisms for the licensing of new
vaccines not registered in the country of manufacture.

Extra read :
https://www.who.int/biologicals/publications/trs/areas/biological_products/W
HO_TRS_822_A2.pdf?ua=1
USA: Food and Drug Administration

India: Central Drugs Standard Control Organization

https://cdsco.gov.in/opencms/opencms/en/biologicals/
https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-documents/Ne
wDrugs_CTRules_2019.pdf
https://cdsco.gov.in/opencms/opencms/en/biologicals/Vaccines/
Different guidelines for vaccine development programs

WHO has also made available several guidelines and reports that are relevant to vaccine
clinical development programmes. These should be consulted as appropriate. They
include:
1. Good clinical practice for trials on pharmaceutical products
2. Good manufacturing practice for pharmaceutical preparations
3. Good manufacturing practice for biological products
4. Guidelines on nonclinical evaluation of vaccines
5. Guidelines on nonclinical evaluation of vaccine adjuvants and adjuvanted vaccines
6. Guidelines on procedures and data requirements for changes to approved vaccines
7. Guidelines for independent lot release of vaccines by regulatory authorities
Recommendations for the evaluation of animal cell cultures as substrates for the
manufacture of biological medicinal products and for the characterization of cell banks
Clinical Considerations for Evaluation of Vaccines for Prequalification
8. The WHO manual Immunization in practice
9. WHO expert consultation on the use of placebos in vaccine trials
Steps

1. Investigational New Drug Applications (INDs)


2. Expanded Access to Experimental Biologics
3. Biologics License Applications (BLA) Process
Details to be included in an IND (typically): (submitted
before the clinical phases)
A complete IND application includes
(1) descriptions of the composition, source, and manufacturing process of the product;
(2) quality control and the methods used to test the vaccine's safety, purity, and
potency;
(3) a summary of all laboratory and preclinical animal testing;
(4) a detailed description of the proposed clinical study; and
(5) names and qualifications of each clinical investigator.

During a 30-day waiting period, the IND application is reviewed by the FDA /NRA to
determine whether human subjects will be exposed to unwarranted risks 
Details to be included in a BLA (typically):

Applicant information
Product/manufacturing information
Pre-clinical studies
Clinical studies
Labeling

Only after IND


Approval and Licensure:

• After a successful Phase III trial, the vaccine developer will submit a
Biologics License Application to the NRA.

• After licensure, the FDA/NRA will continue to monitor the production of


the vaccine, including inspecting facilities and reviewing the
manufacturer’s tests of lots of vaccines for potency, safety and purity.
• The NRA has the right to conduct its own testing of manufacturers’ vaccine
The Licensure Process (typical):
The approval for licensure is based on :
(1) a satisfactory review of all data indicating that the product is safe and effective for its
intended use;
(2) review and acceptance of the manufacturer's labeling;
(3) a satisfactory review of the manufacturer's protocols that summarize the manufacturing
and testing on a specified number of vaccine lots to establish the consistency of the
process;
(4) confirmatory testing on product samples received from the manufacturer; and
(5) a satisfactory inspection of the manufacturer's vaccine production facilities
Details of the trials required
Some terms with trials and reports
1. Immunogenecity
2. Blinding
3. Boostering
4. Randomization
5. Sponsor
6. Vaccine efficacy
7. Vaccine effectiveness
8. Geometric mean titre
9. Confidence interval
10. Adverse event
11. Adverse effect following immunization (AEFI)
12. Adverse event of special interest (AESI)
13. Serious adverse event (SAE)
14. Cluster randomization
15. Attack rate
16. Definition of a case
17. Immunological correlate of protection
18. Preliminary trials
19. Pivotal trials
20. Posology
21. Pharmacovigilance
22. Good clinical practice
23. Good manufacturing practice
24. Seroconversion
25. Responder
26. Responder rate
Pre and post licensing safety
Indian Pharmacopoeia Commission and the Pharmacovigilance
Programme of India

To monitor Adverse Drug Reactions (ADRs) in Indian population.


To create awareness amongst health care professionals about the importance of ADR
reporting in India.
To monitor benefit-risk profile of medicines and vaccines
Generate independent, evidence based recommendations on the safety of medicines.
Support the CDSCO for formulating safety related regulatory decisions for medicine.
Communicate findings with all key stakeholders.
Create a national centre of excellence at par with global drug safety monitoring
standards.
Collaborating with the other international health agencies.
To share the Adverse reaction reported for vaccines to (i) District Immunization Officer
(DIO), (ii) State AEFI Committee and (iii) the National AEFI Committee for examination
and recommendation.
The results of the cases discussed in the Signal Review Panel of the Pharmacovigilance
Programme of India (PvPI) will be shared with AEFI Secretariat and CDSCO. These
results will be used as additional evidence during causality assessment by the CA
subcommittee and finalised by the National AEFI Committee
Vaccine Adverse Event Reporting System

The CDC and FDA established The Vaccine Adverse Event Reporting System in 1990.

The goal of VAERS, according to the CDC, is “to detect possible signals of adverse events
associated with vaccines.”

VAERS is a voluntary reporting system. Anyone, such as a parent, a health care provider,
or friend of the patient, who suspects an association between a vaccination and an
adverse event may report that event and information about it to VAERS.

The CDC then investigates the event and tries to find out whether the adverse event was
in fact caused by the vaccination.

The CDC states that they monitor VAERS data to


Detect new, unusual, or rare vaccine adverse events
Monitor increases in known adverse events
Identify potential patient risk factors for particular types of adverse events
Identify vaccine lots with increased numbers or types of reported adverse events
Assess the safety of newly licensed vaccines
Vaccine Safety datalink:

The CDC established this system in 1990.


The VSD is a collection of linked databases containing information from large medical
groups. The linked databases allow officials to gather data about vaccination among the
populations served by the medical groups. Researchers can access the data by proposing
studies to the CDC and having them approved.

The VSD has some drawbacks.


•The medical groups providing information to VSD may have patient populations that are
not representative of large populations in general.
• Additionally, the data come not from randomized, controlled, blinded trials but from
actual medical practice.
System monitors post licensing :

Phase IV trials
Vaccine Adverse Event Reporting System (AEFI in India)
Vaccine Safety Datalink.

Phase IV Trials

Phase IV trial are optional studies that drug/biologics companies may conduct after a
vaccine is released. The manufacturer may continue to test the vaccine for safety,
efficacy, and other potential uses.
Post-licensing
Manufacture
After a manufacturer has obtained licensure, the vaccine is subject to lot-by-lot release.
The approved license application becomes the standard that a manufacturer must follow.

Depending on the nature and extent of the change, the authority will make a
determination of whether a new license application would be required or a license
amendment to the PLA would suffice.

The shipment of licensed bulk vaccines for export is permitted, provided that the bulk
vaccine is prepared in exactly the same way as specified in the manufacturer's approved
PLA up to the point of shipment.
What happens in a pandemic ??

Extra read: https://crsreports.congress.gov/product/pdf/R/R46399

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