Bte722 4
Bte722 4
Bte722 4
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.
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.”
• 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.
• 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.
• 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.
• 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:
Non-inferiority trials ?
REGULATION OF VACCINES :
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
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
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
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
• After a successful Phase III trial, the vaccine developer will submit a
Biologics License Application to the NRA.
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.
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 ??