Overview of Vaccinology

What is Vaccinology?

  • Vaccinology is the study of vaccines.
  • It includes the study of immunogens used, the immune responses elicited by vaccines and the processes of delivery, manufacturing and evaluation of vaccines.
  • Vaccinology also focuses on safety of vaccines and vaccine trials and the economics, ethics and regulations which surround vaccines.
  • Recently, the focus of vaccinology has diverged to include non-infections diseases including cancers, addictions and neurodegenerative conditions.

What are Vaccines?

  • Chemical or biological substances
  • Designed to stimulate the body’s immune system to generate an immune response
  • The immune response is aimed to confer long-term protection

In general, a vaccine should satisfy the following requirements:

  • Safe (no or few side effects)
  • Easy and cheap to manufacture
  • Stable during storage/transport
  • Easy to administer
  • Could be given to infants (ideally alongside other childhood vaccinations)
  • Would stimulate long-lasting protection against all forms of the targeted disease

 

History of Vaccines

  • The use of vaccines for the prevention of infectious disease developed from the observation that individuals who recovered from a specific infectious disease did not contract the disease again.
  • The intradermal application of powdered smallpox crusts, a process called variolation, was practiced in the Middle East and brought to the Western world by Lady Mary Montagu. This process was effective in inducing protective immunity as a primitive vaccine.
  • Edward Jenner observed that milkmaids who came into contact with cattle infected with cowpox (vaccinia) were solidly protected from smallpox in the late 18th century. Jenner used the less dangerous vaccinia material to inoculate a boy and discovered that he was immune to the subsequent challenge to smallpox.
  • Louis Pasteur developed the first rabies vaccine at the end of the 19th century and established the basic principles to develop vaccines by “isolating, inactivating, and injecting infectious agents”.
  • Large scale vaccine production came after the discovery of safe and reproducible ways to inactivate toxins and pathogens by heat or formaldehyde or by the attenuation of pathogens by passage in vitro.
  • Using these simple technologies vaccines were developed from 1920 to 1980.
  • In the 1980’s vaccine research was catapulted by the advent of recombinant DNA technology. Progress in the field of conjugation technology also provided a critical method for production of more effective vaccines. This technology provided a method for joining a polysaccharide with protein carrier that converted a thymic independent antigen ie. polysaccharide, to a polysaccharide/protein hybrid with thymic-dependent properties. These polysaccharide/protein conjugates enabled production of highly effective vaccines.

 

Vaccine Successes

  • Vaccines are able to eradicate diseases. One of the best examples of this is Smallpox. Smallpox was the first successful vaccine to be developed in 1796. A global vaccination program which started in 1967 led to the eradication of the disease as there have been no reported smallpox cases since 1977.
  • Polio is another disease which is close to eradication due to the development of a polio vaccine. In 1988, the World Health Organization started a vaccine-driven program to eradicate polio. Since this time, polio has been reduced by approximately 99%.
  • Vaccines have an expansive reach. They protect individuals, communities and entire populations.
  • Vaccines have rapid impact. The impact of most vaccines on communities and populations is almost immediate. For example, global measles deaths have decreased by 84% worldwide in recent years. A remarkable decline in the number of deaths due to measles has been observed — from 550,100 deaths in 2000 to 89,780 in 2016.
  • Vaccines save lives and reduce costs associated with diseases. Recently, a panel of distinguished economists put expanded immunization coverage for children in 4th place on a list of 30 cost-effective ways of advancing global welfare (Copenhagen Consensus, 2008).
  • Vaccines have led to the reduction of disease incidence, prevalence, morbidity or mortality to a locally acceptable level as a result of: deliberate efforts to maintain vaccination and continued intervention measures. Examples of diseases which reduced in incidence because of vaccines include pertussis, pneumococcal disease and childhood diarrhoea caused by the rotavirus.

 

Vaccines Currently in Use

There are less than 50 licensed vaccines to date (Table 1). These vaccines have reduced the worldwide burden of disease. Age of administration differs between the different vaccines and the vaccines provided to an individual are dependent on the country they are from as different countries have varying immunization schedules.

[table id=206 /]

Table 1: List of Vaccine Preventable Diseases [WHO – Vaccines and diseases]

 

Future vaccines

  • Although there is a newly licensed malaria vaccine, RTS,S, it has very low efficacy and therefore more effective immunogens must be designed. The challenge with making an effective malaria vaccine lies in the complexity of the malaria parasite. More than 20 potential vaccines are currently in clinical trials.
  • In 2019 three countries, Malawi, Ghana and Kenya have been selected for the malaria vaccine roll-out pilot program. After 30 years of research the RTS,S vaccine is the first malaria vaccine to successfully complete phase 3 clinical trials and provides partial protection for young children against malaria. The RTS,S vaccine pilot program is designed to generate evidence, experience and information that is required by the WHO and policy makers to develop a recommendation on the broader use of RTS,S.
  • There is still no HIV vaccine, more than 30 years after the discovery of the virus. The virus is very complex and always evolving which makes it difficult to develop a vaccine capable of preventing all the different strains of HIV. Currently, researchers are trying to discover what components of the immune system can provide protection against different HIV strains. Once that has been identified, designing a vaccine to stimulate the immune system to produce this response can start.
  • Currently, BCG is the only tuberculosis (TB) vaccine. However, BCG is only able to protect infants from extra-pulmonary TB. Therefore, there is a need for new TB vaccines. Although there are several TB vaccine candidates, most do not make it far through clinical trials and more work needs to be done to understand what immune components protect from TB disease.
  • With the recent Ebola virus outbreaks, more work is being done to produce effective vaccines against these viruses. ZMapp, a cocktail of antibodies was shown to be beneficial in treating patients once they have been infected. Administration of antibodies is known as passive immunization and ZMapp is considered a therapeutic vaccine against Ebola.
  • In 2015 rVSV-ZEBOV Phase II clinical trials started in Guinea focused on vaccinating front-line health care workers. In 2018 – 2019 rVSV-ZEBOV Ebola vaccine is being used in the Democratic Republic of Congo as part of the response to the outbreak under the Expanded Access / Compassionate use protocol. The preliminary results confirm high efficacy of the vaccine.
  • The 2015 Zika virus outbreak in Brazil emphasised the importance of accelerated research and development for a vaccine. WHO continues to monitor the progress of ZIKA candidate vaccines.

 

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Table 2: List of vaccines under development

 

Considerations of vaccine development and introduction

To develop an effective vaccine it is important to consider the following:

  • Identification of the pathogen and its major characteristics, including strains and serotypes, infectivity, virulence, antigenicity, and the nature of essential immunogens
  • The existence of specific techniques for cultivation of the pathogen
  • Identification of suitable non-human models of infection
  • Knowledge of the human immune response to the pathogen, including the duration and type of response (e.g., serum antibody, mucosal antibody, or cell-mediated immunity)
  • Definition of the target population

Pre-clinical vaccine trials: with animals

The first step in vaccine development involves the in vitro discovery of relevant antigens (e.g. by screening compounds). This is followed by the creation of the vaccine concept. The evaluation of vaccine efficacy and safety is then tested in vitro (in cells and tissues) and in vivo (in animals). Once the efficacy and safety of the vaccine has been confirmed, it is produced according to Good Manufacturing Practice (GMP) standards and tested in human trials.

Clinical vaccine trials: with humans

This is process involves rigorous ethical principles of informed consent from volunteers. The emphasis is on vaccine safety, immunogenicity and efficacy.

Includes several steps:

a) Phase I

  • Small-scale trials to assess whether the vaccine is safe in humans and what immune response it evokes

b) Phase II

  • larger-scale trials
  • assess the efficacy of the vaccine against artificial infection and clinical disease
  • also assess safety, side-effects and the immune responses
  • Phase IIa: Pilot to evaluate efficacy and safety in selected populations of patients with the disease or condition to be prevented. Objectives may focus on dose-response, type of patient, frequency of dosing, or numerous other characteristics of safety and efficacy.
  • Phase IIb: Well controlled trials to evaluate efficacy and safety in patients with the disease to be prevented. These clinical trials usually represent the most rigorous demonstration of a medicine’s efficacy.

c) Phase III

  • larger than phase II
  • look mainly to assess the efficacy of the vaccine against artificial infection and clinical disease
  • Vaccine safety, side-effects and the immune response are also studied

d) Phase IV

  • After the vaccine has been licensed and introduced into use
  • Also called post-marketing surveillance
  • Aims to detect rare adverse effects as well as to assess long term efficacy

 

Vaccine evaluation

Pre-licensing (phase I-III)

Vaccine efficacy:

  • Is the percentage reduction in disease incidence between vaccinated vs. unvaccinated groups
  • Under optimal conditions (eg randomised controlled trial RCT)
  • Use of objective and predefined outcomes- e.g. lab-confirmed influenza
  • Designed to maximise internal validity (by randomisation and allocation concealment)
  • Double blind and RCT commonly used to calculate vaccine efficacy
  • Strengths: bias minimised, rigorous, prospective nature and additional outcomes possible
  • Weaknesses: Complexity, expensive and limitations of external validity

Post-licensing (phase IV)

Vaccine effectiveness:

  • Protective ability of a vaccine towards the target disease/outcomes of interest in real life situations
  • Is a “real world” view of how a vaccine (which may have already proven to have high efficacy) reduces disease in a population.
  • Can assess the net balance of benefits and adverse effects of a vaccination program, not just the vaccine itself, under more natural field conditions rather than in a controlled clinical trial
  • Affected by immunisation coverage (rate of the vaccine uptake)
  • May be affected by other non-vaccine related factors

Many study designs can be used to calculate this measure:

  • Case-control study
  • Screening method
  • Cohort study
  • Household contact study
  • Effectiveness = 1 – [PCV x (1-PPV)] / [(1-PCV) x PPV] = (1-OR) x 100
    If:
    PCV= vaccination coverage in cases
    PPV= Population vaccination coverage

Quiz

Now test your knowledge with these questions!

Related Talks

Jenna Patterson, VACFA – Hepatitis A Vaccination

Dr Jerusha Naidoo, Southern Africa Regional Vaccines Medical Lead at Pfizer – Pneumococcal Vaccines

References

  1. Benjamin Kagina – MPH Lecture – Vaccines – University of Cape Town (UCT) – 17th August 2017
  2. Gregory Hussey – Vaccinology: Global & African perspective – 12th Annual African Vaccinology Course (2016) – 8th November 2016
  3. Barret 2016. Vaccinology in the twenty-first century.Vaccines
  4. World Health Organisation. 2017. Immunization, Vaccines and Biologicals: Vaccines and diseases
  5. WHO – Immunization, Vaccines and Biologicals