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

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, between 2000 and 2008, vaccination against measles reduced global deaths by 78% (from 750 000 deaths to 164 000 deaths per year).
  • 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 incidence because of vaccines include pertussis, pneumococcal conjugate vaccines and rotavirus vaccines

 

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.

 

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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.
  • 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 discovery 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 and Zika virus outbreaks, more work is being done to produce effective vaccines against these viruses. ZMapp is a cocktail of antibodies which has been shown to be beneficial in treating Ebola once it has already infected the individual. Administration of antibodies is known as passive immunization and ZMapp is considered a therapeutic vaccine.

 

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 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:

  • % reduction in disease incidence (vaccinated vs. unvaccinated) groups
  • Under optimal conditions (eg randomized controlled trial RCT)
  • Use of objective and predefined outcomes- eg lab-confirmed influenza
  • Designed to maximize internal validity (by randomization 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 immunization 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

 

Targeted Vaccination

Infant Immunization

  • Vaccines are usually recommended for the youngest age group at risk of experiencing the disease for whom efficacy and safety have been demonstrated.
  • An immunisation schedule is a schematic of the ideal timing of administration of one or more vaccines, based on the best opportunity to provide protection and minimize risk in the prevention of vaccine preventable diseases.
  • The recommended childhood immunization schedule is designed to protect infants and children early in life, when they are most vulnerable. Infants are born with highly regulated immune systems, making it difficult for them to effectively respond to the infectious pathogens encountered shortly after birth. As infants are the most susceptible to pathogens, immunization was originally focused on babies and their protection.
  • The Expanded Programme on Immunization (EPI), with recommended guidelines established by the World Health Organization, is a major international effort to increase the proportion of children covered by basic immunizations against childhood diseases.
  • The first diseases targeted by the EPI were diphtheria, whooping cough, tetanus, measles, poliomyelitis and tuberculosis. Global policies for immunization and establishment of the goal of providing universal immunization for all children by 1990 were established in 1977.
  • Vaccines not only protect the immunized, but can also reduce disease among unimmunized individuals in the community through “indirect effects” or “herd immunity”. Herd protection of the unvaccinated occurs when a sufficient proportion of the group is immune. The decline of disease incidence is greater than the proportion of individuals immunized because vaccination reduces the spread of an infectious agent by reducing the amount and/or duration of pathogen shedding by vaccinees, retarding transmission.

 

WHO recommended childhood vaccines

  • BCG
  • Hepatitis B
  • Polio
  • DTP
  • Hib
  • PCV
  • Rotavirus
  • Measles
  • Rubella
  • HPV

WHO Childhood Immunization Schedule – Recommended Routine Immunizations for Children

CDC Childhood Immunization Schedule – Immunization Schedules for Infants and Children

 

Challenges in eliciting vaccine-induced immunity in infants

Eg. measles vaccine

  • Optimal timing depends on:
    • Rate of disappearance of passively acquired maternal antibodies – as these can interfere with the infant’s immune response
    • Risk of exposure to measles virus
  • At birth and in the first 6 months of life, most infants have passive immunity to measles because of maternal measles antibodies. These antibodies interfere with the immune response to live virus measles vaccine by limiting vaccine virus replication.
  • In many developing countries, where measles is highly endemic and frequently affects infants, routine measles vaccination is recommended at age 9 months. In regions and countries where measles is less common and usually not occur in infants, measles vaccine is recommended routinely at age 12 to 15 months.
  • A second dose of measles is recommended to induce immunity in children who might have failed to mount a sufficient immune response to the first dose.

 

Pre-Adolescent and Adolescent Vaccination

  • Immunization is the most successful public intervention to protect individuals and the community against vaccine preventable diseases.
  • Adolescent immunization has been relatively neglected, leaving a quarter of worlds population under-immunized and vulnerable to a number of vaccine preventable diseases.
  • Vaccinating older age groups will address waning of immunological response – booster doses for some vaccines routinely given during infancy and early childhood because immunity wanes over time. Additional doses can increase the duration of protection through later adolescence and adulthood eg. Tetanus
  • Missed or incomplete vaccination, and the vaccine preventable disease is still a threat in adolescence and beyond.

 

Important Adolescent vaccines

  • Primary Immunization
    • HPV
  • Catch-up Immunization
    • Hepatitis B
    • Measles
  • Booster dose Immunization
    • Meningococcal
    • Pertussis
    • Tetanus
    • Diphtheria

WHO Immunization Schedule – Recommendations for Routine Immunization

CDC Adolescent Immunization Schedule – Immunization Schedules for Preteens and Teens

 

Challenges of delivering vaccination services to adolescents

  • In Africa, there is no established platform or EPI to deliver vaccines to adolescents
  • Cost
  • Access – delivery strategies are difficult to put into place
  • Time for parents (economic cost- time off work)
  • Mass campaigns are periodical and often organised through schools

 

Adult Immunization

  • We vaccinate adults as a prevention to avert health spending, to reduce morbidity and mortality.
  • Vaccines are seen as a solution for national and economic security.
  • Adult vaccination occurs to prevent disability – adding years to life in the elderly.
  • We vaccinate adults 65 years and older due to immunosenescence, which refers to the gradual deterioration of the immune system brought on by ageing. It involves the person’s ability to respond to infections and the development of long-term immune memory, especially by vaccination. It is considered a major contributory factor to the increased frequency of morbidity and mortality among the elderly.
  • New vaccines that are developed must be delivered to the population. Adults would not have received these during their childhood and therefore must be targeted.

 

Adults recommended to receive Vaccinations

  • Persons older than 65 years
  • Health care workers
  • Anatomic or functional asplenia
  • CSF leak
  • Diabetes mellitus
  • Chronic pulmonary disease
  • Advanced cardiovascular disease
  • Immunocompromising conditions
  • HIV+
  • Chronic use of glucoccorticoids
  • Pregnant Women

WHO Immunization Schedule – Recommendations for Routine Immunization

CDC Adult Immunization Schedule – Immunization Schedules for Adults

 

Challenges of delivering vaccination services to adults

  • There is no established EPI or delivery schedule to vaccinate adults
  • Vaccination services are inconvenient to adults
  • Adults are less aware of the importance of vaccination and the availability of vaccines
  • There is less education available on adult vaccination
  • Vaccines are seen as a ‘childhood’ medical service

 

Vaccination in Pregnant Women

  • Pregnancy is an immunologically altered state which renders women more susceptible to infections.
  • Maternal immunization aims to protect:
    • pregnant women
    • the fetus or infant
    • or both mother and child
  • Maternal immunization is an effective strategy to protect mothers from diseases that are particularly severe during pregnancy and to protect against vaccine preventable infections in early infancy.
  • Maternal antibody is actively transported across the placenta and serves to provide protection to the newborn during the first weeks to months of life.
  • Some childhood immunizations are not always able to protect newborn infants and these are therefore administrated later, except BCG and polio.
  • Babies under 6 months too young to be vaccinated for tetanus, pertussis, influenza so these are given to the mothers’ during pregnancy instead and therefore offer newborns protection.

Vaccines that are safe in pregnancy

  • Influenza
  • Tetanus
  • Pertussis
  • Diphtheria
  • Hepatitis A & B
  • Meningococcal

WHO Immunization Schedule – Recommendations for Routine Immunization

CDC Pregnancy and Vaccination – Guidelines for Vaccinating Pregnant Women

 

Success in vaccinating pregnant women

  • The biggest maternal vaccination success story – on a global scale – is against tetanus, the deadly infection marked by muscle spasms caused by a bacterium in the soil getting into a wound.
  • More than one million people died each year from tetanus in the 1980s, about three-quarters of them infants in the first month of life.
  • Today, the toll of neonatal deaths has been reduced by over 90% and maternal and neonatal tetanus has been eliminated from all but 22 countries.

 

Challenges of delivering vaccination pregnant women

  • Concern about the safety of vaccines given during pregnancy – among both the public and healthcare providers
  • Doubt about the effectiveness of the vaccine
  • Lack of knowledge and education about the burden of diseases
  • Inadequate facilities and staffing, vaccine purchase and storage, and reimbursement for vaccination
  • Lack of a strong and unequivocal recommendation by healthcare professionals, government, and advisory bodies

 

Vaccination in HIV+ Persons

  • Compared with HIV- individuals, HIV+ adults often have an increased risk of infection or experience more severe morbidity following exposure to vaccine-preventable diseases.
  • Improved health and prognosis mean that HIV+ adults are also increasingly likely to engage in travel or occupations that carry a risk of exposure to infectious agents.
  • Immune responses to vaccination are often sub-optimal in HIV+ patients, and while these improve with ART, they often remain lower and decline more rapidly than in HIV- individuals.
  • However, many of these vaccines still afford protection and for some vaccines it is possible to improve immunogenicity by offering modified vaccine schedules, with higher or more frequent doses, without compromising safety.
  • Generally administering live (replicating) vaccines in people who are immunocompromised is avoided as HIV infection dysregulates antigen-induced immunity.
  • However, it is often safe to use replicating vaccines in HIV+ patients who are not immunocompromised.
    • HIV+ adults with CD4 cell counts below 200 cells/μL must not be given replicating vaccines due to a potential risk of vaccine-associated disease; when indicated, vaccination should be postponed until the CD4 cell count has improved on antiretroviral therapy.
    • HIV+ adults with a CD4 cell count of 200–350 cells/μL have moderate immunodeficiency. Clinical judgement should guide the use of replicating vaccines in these patients. Where exposure is likely, natural infection often carries a greater risk of adverse outcomes than vaccination (e.g. measles, chickenpox), making the offer of vaccination the preferred option. Antiretroviral therapy improves the safety and immunogenicity of vaccination in this group.
    • With the exception of the MMR (measles, mumps, rubella) vaccine, co-administration of multiple replicating vaccines is not recommended due to uncertainties over safety and efficacy. An interval of at least 4 weeks between vaccinations is recommended.
    • Regardless of the CD4 cell count, contraindications to the use of replicating vaccines that apply to the general population (e.g. in relation to the use of immunosuppressive therapy) also apply to HIV+ patients.

 

Common vaccines recommended to HIV+ persons

  • Influenza
  • DTP
  • HPV
  • Varicella
  • Zooster
  • MMR/Measles
  • Pneumoccocal
  • Hepatitis A
  • Hepatitis B
  • Meningoccocal

CDC HIV+ Vaccination – HIV Infection and Adult Vaccination

 

Challenges in delivery vaccines to HIV+ persons

  • There is no established immunization platform or EPI
  • HIV+ patients may be “presumed” healthy and not vulnerable to vaccine preventable diseases however, the depletion of antigen-specific T and B cells in HIV+ persons increases their risk to vaccine preventable diseases
  • HIV co-infections
  • HIV infection is prevalent among adolescents and adults, however HIV+ adolescents have the least contact with health facilities
  • The epidemiology of vaccine preventable diseases among HIV+ adolescents and adults is not well characterized in Africa

 

Challenges Facing Vaccination

Key components of a vaccination program

Immunization programs are crucial to ensure vaccines get used optimally.

  • Service Delivery
  • Vaccine Supply, Quality and Logistics
  • Surveillance and monitoring
  • Advocacy and Communication
  • Programme management

Service delivery

Parameters for this component includes:

  • Vaccination coverage (data)
  • Drop out rates eg. BCG to DTP1; DTP1 to DTP3 (data)
  • Existence of a national immunization plan (policy)

 

Challenges in Africa

  • Low vaccination coverage in Africa may explain the burden of vaccine preventable diseases (VPDs)
  • Progress has been made in immunization in Africa since Expanded Program on Immunization (EPI) was initiated. Some of the key achievements include:
    • An increase of the DTP3 containing vaccine to 76 % in 2015
    • The decline in Measles deaths by 86% from 2000 to 2014
    • Acceleration of the introduction of new vaccines
  • However, in Africa, 1 in 5 children does not receive the most basic vaccines they need and progress in vaccination coverage has also recently stalled.

Vaccine supply, quality and logistics

Parameters for this component and challenges in Africa

  • Availability of services (financing, HR)
    • Human resources, maintenance and vaccination campaigns:
      • Not enough personnel, limited training opportunities
      • Ongoing maintenance exacerbated by “load shedding”
    • Campaigns increases the complexity of logistics
  • Guidelines (policy)
    • Successful national immunization programmes depend on up-to-date policies and effective strategies in order to achieve and sustain their goals
    • When the EPI was established over 40 years ago, its focus was on vaccinating infants with a limited number of traditional vaccines
    • Today the vaccine world has changed dramatically
    • National Immunization Technical Advisory Groups (NITAGS) give advise and make recommendations
  • Optimal cold chain management (financing, HR)
    • There are multiple sources of financing and multiple procurement streams, including selfpurchase by countries and purchases by international organizations
    • Wastage of up to 50% in the past! Which is not sustainable with newer, many and more expensive vaccines
    • High-quality supply chain systems are complex and require continued investment
    • When one vaccine is added to an existing vaccination programme, storage and delivery capacity in many countries quickly become overstretched
    • Multiple products, entities and responsibilities in both the public and private sectors should be involved, which is complex
  • Vaccine stock forecasting (data)
    • Reliable data is essential to manage stockouts – stockouts are missed opportunities to vaccinate which leads to low coverage
    • Many countries do not have reliable data about past vaccine usage or accurate projections of target populations and their locations
  • Quality of vaccines (policy)

 

In developing countries, supply chain comprises of:

  • The segment that moves vaccines from suppliers to the receiving country.
  • The segment that moves vaccines in country from the port of entry through the national and local storage and distribution system to the health care provider.
  • Safe and timely distribution of vaccines is associated with great challenges- risks include the quality of the vaccines.

 

Surveillance and monitoring

Parameters for this component includes:

  • Completion and timeliness (data)
  • Reported new cases (data, financing)
  • Mortality, morbidity, CFR etc (data)
  • Feedback of collected data
  • Development of monitoring indicators (data, policy)
  • Systems for AEFI (identify, investigate, respond – data)

 

Further information

  • Efficient surveillance and response systems can prevent small outbreaks from developing into uncontrollable, larger outbreaks.
  • Surveillance and monitoring can also help avoid or mitigate the negative implications of real or perceived side effects of vaccination.
  • New information technologies can ensure that valid and accurate data is collected, so that under – and unvaccinated groups are detected and reached, avoiding outbreaks in specific locations or population groups.

Advocacy and communication

Parameters for this component includes:

  • Social mobilization, advocacy and communication
  • Communication plan for hard to reach populations
  • Engagement plan for key stakeholders (beyond MoH)
  • Information, Communication and Education materials
  • Budget (financing) for activities and materials
  • Commitment of broad and high-level decision makers

Further information

  • The public must receive information about the risks of VPDs.
  • Understanding the benefits and risks of vaccination can enhance trust in vaccines, immunization services and health authorities.
  • Tailored strategies based on reliable research and evidence are crucial to stimulate demand for vaccines.
  • Research and improved immunization data to monitor perceptions, knowledge and attitudes are crucial to ensure equitable extension of services.

Programme management

Parameters for this component includes:

  • Government funding (financing)
  • Adequacy of personnel (numbers and skills)
  • Micro plans for each district (policy)
  • Reports on the implementation of plans (M&E)
  • Assessment of services conducted (M&E)
  • Supportive supervision visits conducted (M&E)

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