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Presented at a lecture for Clinical Research Coordinators held at King Fahad Medical City on Sunday June 11, 2020, 13.00-14.00 By Professor Omar Hasan Kasule MB ChB (MUK), MPH (Harvard), DrPH (Harvard) Chairman of the Institutional Review Board
INTRODUCTION
• Vaccination is the process of inoculation that produces immunization. The antigen is a component of the bacterium or virus against which an antibody is formed
• In 1954 the Salk inactivated polio vaccine was tried in a field trial. In the 1960s Dr. Sabin developed a weakened (attenuated vaccine) called the Oral Polio Vaccine (OPV) that is given orally and is the one used now. OPV gives better immunity but being a live vaccine can revert to the wild form and cause disease in children – a few in a million
• In the 1918 Spanish flu that killed 100m the only remedy was a transfusion of blood from recovered patients
• Starting in 1931 the influenza virus was grown in embryonated eggs and in the 1940s inactivated vaccine was developed. In 2012 vaccines made from cell cultures were approved and later vaccines were made using recombinant DNA techniques.
• The influenza virus changes every season requiring a new vaccine. The older vaccine is less effective.
STAGES OF VACCINE DEVELOPMENT: Preclinical phase in the lab and animals
• Identification and isolation of the antigen
• Production of the vaccine either in animals or in the laboratory
• Testing the vaccine in test tubes and animals
• Manufacture of the vaccine according to Good manufacturing standards
References:
- http://www.euvaccine.eu/vaccines-diseases/vaccines/stages-development
- World Health Organization’s (WHO’s) Development of New Vaccines
- https://www.cdc.gov/vaccines/basics/test-approve.html
STAGES OF VACCINE DEVELOPMENT: clinical phase testing in humans
• Phase 1 clinical trials: small trials in healthy volunteers of the same age and gender as the targeted patients to test the safety and evoking immunity. Vaccines for children are first tested in adults. In a few cases, the experimental group may be challenged with an attenuated or modified version of the pathogen
• Phase 2 clinical trials: in a large group of individuals at risk of getting the disease. patients with the infection to test efficacy (immune response), proposed dose, schedule of immunization, method of delivery, safety, adverse effects. The trial is blinded, randomized, and includes a placebo.
• Phase 3 clinical trials: test the vaccine in a large number of people in tens of thousands with the aim of testing is to assess safety and efficacy (prevent disease, prevent infection, producing antibodies).
• Approval and licensing the use of the vaccine for use followed by manufacturing under quality control
• Phase 4 post-marketing trials involve long-term monitoring of efficacy and safety.
THE SALK POLIO VACCINE TRIALS 1BMJ. 1998 Oct 31; 317(7167): 1233–1236.
• Dr. Salk was made by cultivating 3 strains of the polio vaccine in monkeys. The virus was then separated and was killed using formaldehyde. The Salk vaccine was called the Inactivated Polio Vaccine (IPV)given by injection
• On 23 January 1953, Jonas Salk of Pittsburgh presented the results of his tests of a “killed virus” polio vaccine on 161 children. The level of antibodies in the blood rose and the children had no adverse effects
• In 1954 Across the United States, 623 972 schoolchildren were injected with vaccine or placebo, and more than a million others participated as “observed” controls.
• The results, announced in 1955, showed good statistical evidence that Jonas Salk’s killed-virus preparation was 80-90% effective in preventing paralytic poliomyelitis.
SOME OF THE CHILDREN WHO PARTICIPATED IN THE SALK VACCINE TRIAL
Figure
“Polio pioneers”—some of the many children who took part in trials of poliomyelitis vaccine
INFLUENZA VACCINE
Sanay Sesay et al. Safety, Immunogenicity, and Lot-To-Lot Consistency of a Split-Virion Quadrivalent Influenza Vaccine in Younger and Older Adults: A Phase III Randomized, Double-Blind Clinical Trial. Hum Vaccin Immunother 2018 Mar 4;14(3):596-608.
• Comparison of the IIV4 against the IIV3 in the Northern hemisphere influenza season of 2014-2015.
• Younger (18-60) and older (>60yr) adults were randomized 2:2:2:1:1 to receive various 3 lots of IIV4 or 2 lots IIV3 influenza vaccines.
• 21 days after vaccination hemagglutination antibodies were measured. Seroprotection rates were >98% in the younger and >90% in the older adults. There were no differences between the two vaccines and the various lots.
• IIV4 and IIV3 had similar safety profiles
MEASLES VACCINE
Shahrokh Izadi et al. Head-to-head Immunogenicity Comparison of Edmonston-Zagreb vs. AIK-C Measles Vaccine Strains in Infants Aged 8-12 Months: A Randomized Clinical Trial. Vaccine 2018 Jan 29;36(5):631-636
• A non-inferiority multi-center parallel randomized double-blind trial to compare the EZ vs AIK-C strains of measles vaccines.
• 200 infants aged 8-12 months were randomized to EZ and AIK-C measles vaccines. Blood samples were taken before and 60 days after the vaccination. The outcome was anti-measles antibodies
• Seroconversion was 76.1% for EZ and 58.7% for AIK-C.
HUMAN PAPILLOMAVIRUS VACCINE
Elmar A Joura et al. A 9-valent HPV Vaccine Against Infection and Intraepithelial Neoplasia in Women. N Engl J Med 2015 Feb 19;372(8):711-23.
• HPV vaccine is made against 9 strains of the virus (6, 11, 16,18, 31, 33, 45, 52, and 58).
• Efficacy and Immunogenicity were studied in 14,215 women aged 16-26 years in a phase 2/3 randomized, international, double-blind study.
• Intramuscular injections were given on day 1, month 2, and month 6. Serum was collected for analysis of antibodies. Swabs of the labia, vulva, perineum, and cervix were obtained for HPV DNA testing and for cytology (PAP smear).
• Results showed that the vaccine prevented disease and generated antibody response.