Immunological basis of Vaccination

Introduction

Immunization aims to artificially induce immunity against disease. This may be active, whereby the immune system is recruited to provide protection against the disease or infection, or passive, where exogenous protection is provided, albeit temporarily.

Normal immune response

The immune system provides protection against infectious agents. Classically, the system is divided into the innate immune system and the specific or acquired immune system. The innate immune system consists of cells (monocytes, macrophages, dendritic cells, neutrophils, eosinophils and natural killer cells) and molecules (complement, cytokines, chemokines etc) while the specific immune system is composed of lymphocytes. These include B lymphocytes producing antibody, and subsets of T lymphocytes including CD4+ T lymphocytes and CD8+ cytotoxic T lymphocytes. The CD4+T lymphocytes are further divided into TH1 cells producing inflammatory cytokines such as interferon Ɣ (IFN Ɣ ) and TH2 cells, as well as regulatory T cells and TH17 cells1,2.

The innate immune system recognizes the pathogen and subsequently activates the specific immune system3. Then these two systems act in concert against the infection. Pathogens that enter the body through skin/ mucous membranes are taken up by resident antigen presenting cells in these tissues. The main antigen presenting cell (APC) is the dendritic cell, the macrophage being another APC. The antigen presenting cells and molecules of the innate immune system have receptors (pattern recognition receptors) that can recognize conserved foreign molecules found only on pathogens (pathogen associated molecular patterns). Recognition is followed by activation of these cells and molecules. Dendritic cells along with the macrophage, found in the skin and othersites are crucial in the subsequent activation of the specific immune system1. The dendritic cell senses potential ‘danger’ when recognizing pathogen associated molecular patterns. Recognition is followed by uptake of the pathogen and activation of the dendritic cell and other antigen presenting cells.

This leads to,

• production of cytokines and chemokines resulting in inflammation

• up-regulation of co-stimulators on the antigen presenting cells essential for successful antigen presentation to T cells

• localization of the pathogen containing antigen presenting cells to the draining lymph node.

Blood borne pathogens are directly taken up by dendritic cells in the white pulp of the spleen.

During this process, the dendritic cells internalize the pathogens and present peptides derived from the microorganisms, in conjunction with major histocompatibility complex (MHC) class II molecules on its surface. Viruses infecting dendritic cells produce virus coded peptides in the cytoplasm. These peptides are presented in conjunction with MHC Class I molecules.

T and B cells have receptors that recognize antigen. Most circulating lymphocytes recognize non self-antigen2. Lymphocytes circulate in the body between blood and peripheral lymphoid tissue (cell trafficking). Activated dendritic cells present peptides derived from pathogens, in conjunction with MHC Class II molecules to CD4+ T cells in the T cell areas of the lymph nodes and spleen. The CD4+ T cell will be activated only if second signals are provided by co-stimulatory molecules on the surface of dendritic cells. These co-stimulators are up regulated only if pathogen associated molecular patterns are recognized by the dendritic cells. As these patterns are only found on pathogens, the dendritic cell will activate non-self reacting CD4 +T cells. Depending on the pathogen and the cytokine milieu around the reaction, the CD4+ T cells become either armed effector TH1 or TH2 cells or memory cells (2).

Dendritic cells which are activated by microorganisms such as M. tuberculosis produce cytokines that switch a naïve CD4+ T cell to an activated TH1 cell, while helminths and some bacterial pathogens induce a TH2 response. TH1 cells produce cytokines (IL2, IFN Ɣ) that activate CD8+cytotoxic T lymphocytes, macrophages and B lymphocytes, while TH2 cells activate B cells by producing IL4, 6 and 13.

B cells that recognize protein antigens need help from CD4+ T cells (TH1 and TH2) to produce antibody. The initial B cell response takes place extra follicularly (outside the germinal centre)2 and produces low affinity IgM and a small amount of IgG. This occurs within a few days of the infection/immunization and is short lived.This is followed by a response in the germinal centre. B cells move into the germinal centre and encounter their cognate antigen found on the surface of follicular dendritic cells. The B cell proliferates, producing a clone of daughter cells whose antigen binding receptors (immunoglobulin molecules found on the surface of the B cell) have undergone point mutations (somatic hypermutation). These mutations are confined to the antigen binding site of the receptor. B cells with receptors with a greater fit (affinity) would bind to the cognate antigen and survive, while those with a weaker fit would undergo apoptosis. The surviving B cells would differentiate into plasma cells or memory B cells. With time, high affinity (affinity maturation) IgG, IgA and IgE antibodies are produced (isotype switching) by plasma cells, some being long lived. Memory B cells are capable of producing high affinity, class switched antibody with great rapidity, after re-exposure to the same microorganism. Affinity maturation, isotype switching and memory need T cell help and are hallmarks of antibody responses to protein antigens. T cell help is provided in germinal centers by follicular helper T cells (TfH cells). This response takes 10-14 days to appear and terminates in 3-6 weeks. Peak antibody concentrations occur 4-6 weeks after primary immunization.

Polysaccharide epitopes such as the capsules of S pneumoniae and H influenzae, do not activate CD4+ T cells (T independent responses) (2). A subset of B cells in the marginal zone of the spleen, assisted by marginal zone macrophages, produce low affinity mainly IgM antibodies and medium affinity IgG (T independent antibodies). Polysaccharides arepoorly immunogenic in children under 2 years, till maturation of the marginal zone. As T independent responses do not produce memory cells, subsequent re-exposure evokes a repeat primary response. In some instances, revaccination with certain bacterial polysaccharides may even induce lower antibody responses than the first immunization, aphenomenon referred to as hyporesponsiveness (4).

Antibodies provide protection against extra cellular organisms, such as capsulate bacteria or viruses during an extra cellular phase. IgA provides mucosal immunity, preventing infection by bacteria and viruses through the mucosa; IgM provides quick responses to blood borne pathogens while IgG protects blood and tissues.

Protection against intracellular microorganisms is through cell mediated immunity. Viruses infect cells and produce virus derived proteins in the cytoplasm. Peptides derived from these proteins are presented on MHC Class I molecules by all nucleated cells. These are recognized by previously activated cytotoxic T lymphocytes and the infected cell is destroyed. Microorganisms residing in intracellular vesicles of macrophages such as M tuberculosis, are dealt with by TH1 cells activating the macrophage, resulting in intracellular killing of the bacteria.

Vaccines

Different types of vaccines have been produced (5).

• Live attenuated

• Killed/inactivated

• Subunit

• Recombinant

• Conjugate

Immune response to vaccines

Vaccine induced immunity is mainly due to IgG antibodies. Antibodies are capable of binding toxins and extracellular pathogens.The quality ofthe antibody (avidity), the persistence of the response and generation of memory cells capable of a rapid response to reinfection are key determinants of vaccine effectiveness. For protection against bacterial diseases that result from the production of toxins (tetanus and diphtheria) the presence of long lasting antitoxin antibody and memory B cells are necessary, ensuring the presence of antitoxin antibody at the time of exposure to the toxin. With viruses such as hepatitis B, undetectable antibody titers are seen in many vaccine recipients but due to the long incubation period of the virus, memory B cells can be reactivated in time to combat the infection.

For infections which originate at mucosal sites, transudation of serum IgG will limit colonization and invasion. This is due to pathogens being prevented from binding to cells and receptors in the mucosa. Transudation of IgG is not seen with polysaccharide vaccines. If the pathogens breach the mucosa IgG in serum will neutralize the pathogen, activate complement and facilitate phagocytosis, thereby preventing spread. Some vaccines (eg. oral polio, rotavirus and nasal influenza) will stimulate production of IgA antibody at mucosal surfaces and thereby limit virus shedding. Live, inactivated and subunit vaccines evoke a T dependent response, producing high quality antibody and memory B cells. Polysaccharide vaccines (eg. pneumococcal 23 valent vaccine) evoke a T independent response4 where the IgG produced is of poor quality (affinity) and memory B cells are not produced. However, conjugation of the polysaccharide with a protein (conjugate vaccines) evokes a T dependent response. Inactivated, subunit and conjugate vaccines will only evoke antibodies. Live viral vaccines will in addition activate cytotoxic T lymphocytes. These cytotoxic T lymphocytes limit the spread of infections by killing infected cells and secreting antiviral cytokines.

Antibody responses are ineffective against intracellular organisms such as M. tuberculosis. There is evidence that a CD4+TH1 response, with production of IFN  Ɣ leading to activation of infected macrophages is elicited following BCG vaccination(6).

The quality of the immune response depends on the type of vaccine. Live viral vaccines evoke a strong immune response.

This is due to(7)

• having sufficient pathogen associated molecular patterns to efficiently activate immature dendritic cells, a key requirement for the development of specific immunity.

• the vaccine virus multiplying at the site of inoculation and disseminating widely, and being taken up by dendritic cells at many sites. These dendritic cells are then activated and are carried to many peripheral lymphoid organs, where activation of antigen specific B and T lymphocytes occur. As the immune response occurs at multiple sites, live viral vaccines evoke a strong immuneresponse persisting for decades. Due to the early and efficient dissemination of the virus, the site or route of inoculation does not matter (eg. SC versus IM). BCG vaccine acts similarly, by multiplying at the site of inoculation and at distant sites as well. Non-live vaccines may have enough pathogen associated molecular patterns to activate dendritic cells but in the absence of microbial replication this activation is limited in time and is restricted to the site of inoculation. As the immune response is restricted to the local lymph nodes, it is weaker than with a live vaccine. Therefore, repeated booster doses are necessary. As only the regional nodes are involved, multiple non live vaccines can be given, provided the inoculations are performed at different sites. Booster doses are ineffective with polysaccharide vaccines as memory B cells are not produced.

In addition, the route of inoculation is important. The dermis has many dendritic cells, and for example, the rabies vaccine given intradermally at 1/10th the IM dose can evoke an equally good response. Where the vaccine is not very immunogenic (eg. hepatitis B vaccine), IM injections are preferred over SC7,8 as muscle tissue has many dendritic cells, unlike adipose tissue.

Determinants of primary vaccine response

• Intrinsic immunogenicity of the vaccine.

• Type of the vaccine – Live viral vaccines elicit better responses than non-live vaccines. Non-live vaccines rarely induce high and sustained antibody responses after a single dose. Therefore, primary immunization schedules usually include at least two doses, repeated at a minimum interval of 4 weeks to generate successive waves of B cell responses. Even so, the response usually wanes with time.

• Dose – As a rule, higher doses of non-live antigens, up to a certain threshold, elicit higher primary antibody responses. This may be particularly useful when immunocompetence is limited eg. for hepatitis B immunization of patients with end stage renal failure.

• Nature of the protein carrier.

• Genetic composition of the individual.

• Age – responses at the extremes of age are weaker and less persistent.

Determinants of duration of vaccine response(7)

Plasma cells which produce antibodies are usually short lasting, while a few plasma cells produced in the germinal centre may survive for long periods in the bone marrow. These cells are responsible for the maintenance of protective antibodies for long periods. This occurs most efficiently with live vaccines, less efficiently with non-live vaccines, but not with polysaccharide vaccines. Live viral vaccines are the most efficient at evoking long lasting immune responses that may persist lifelong due to the presence of viral antigens that may regularly activate the immune system.

Interval between doses may be important. Two doses given one week apart may evoke a rapid short lived response, whereas 2 doses 4 weeks apart may be longer lasting. Vaccination at extremes of age or in patients with chronic disease may evoke short lived responses.

Adjuvants (9)

For non-live vaccines, adjuvants are incorporated to provide the ‘danger’ signal to the antigen presenting cells. Adjuvants are also needed to prolong the antigen delivery at the site of inoculation, thereby recruiting more dendritic cells. They should also be non-toxic.

The known adjuvants used in human vaccines are,

• Alum – an aluminum salt-based adjuvant.

• AS04 – a combination adjuvant composed of monophosphoryl lipid A adsorbed to alum.

• Oil-in-water emulsions – such as MF59 and AS03

Summary

All vaccines produce antibodies which can neutralize extracellular pathogens. Conjugate vaccines, toxoids, inactivated vaccines and live attenuated vaccines produce high affinity antibody and memory cells unlike polysaccharide vaccines. Polysaccharide vaccines are made more immunogenic by conjugation with a protein carrier.

Live viral vaccines evoke cytotoxic T lymphocyte responses which act against intracellular pathogens. Similarly, the BCG vaccine activates TH1 cells, whose cytokines help macrophages control M. tuberculosis. Live viral vaccines produce long lasting, even lifelong immunity compared to non-live vaccines.

References

1. Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol 2010; 125: S24-32.

2. Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol 2010; 125: S33-40.

3. Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science 2010; 327: 291-95.

4. Pace D. Glycoconjugate vaccines. Biol. Ther 2013: 13(1): 11-33.

5. Pulendran B, Ahmed R. Immunological mechanisms of vaccination. Nat Immunol 2011; 12(6): 509-17.

6. Ritz N, Hanekom WA, Robins-Browne R, Britton WJ, Curtis N. Influence of BCG vaccine strain on the immune response and protection against tuberculosis. FEMS Microbiol Rev 2008; 32: 821-841.

7. Siegrist CA. Vaccine Immunology. In: Plotkin SA, Orenstein W, Offit PA Eds. Vaccine Expert Consult 6th Ed Sauders 2012, p 15-32. 8. de Lalla F, Rinaldi E, Santoro D, et al. Immune response to hepatitis B vaccine given at different injection sites and by different routes: a controlled randomized study. Eur J Epidemiol 1988; 4: 256-8.

9. Alving CR, Peachman KK, Rao M, Reed SG. Adjuvants for human vaccines. Curr Opin Immunol 2012; 24(3): 310-15. Dr Rajiva de Silva Dip. Med. Micro, MD(Micro.) Consultant Immunologist, Medical Research Institute, Colombo

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Precautions and Contraindication before vaccination

There are many reasons to avoid or postpone vaccines.Sometimes people may have unreasonable concerns that lead to indecision to get vaccination even when there is no risk.  It is critical for vaccine providers and relevant healthcare workers to distinguish among these different reasons. In this article we try to make rough idea about this facts. Before that lets refresh the terms "Contraindication " and "Precaution ".

A contraindication is a situation in which a drug, such as a vaccine, should not be used because the risk outweighs any potential therapeutic benefit.

A precaution is a condition that may increase the risk of an adverse reaction following immunization or that may compromise the ability of the vaccine to produce immunity. In general, vaccines are deferred when a precaution is present. However, there may be circumstances when the benefits of giving the vaccine outweigh the potential harm, or when reduced vaccine immunogenicity may still result in significant benefit to a susceptible, immuno-compromised host.

1. Vaccines should not be administered
if there was a severe reaction such as anaphylaxis following administration of that particular vaccine or a component of that vaccine.

2. Live vaccines should not be administered
• to a person having a malignancy of the reticulo-endothelial system
• during pregnancy
• if a live vaccine had been administered within one month
• if the person has had blood or blood products including immunoglobulin within three months
• for two weeks after stopping long term oral steroids ( >= 2mg/kg /day prednisolone or equivalent or 20 mg / day for > 2 weeks in children or 40 mg/day > 2 weeks in adults)
• for three months after stopping immunosuppressive therapy varicella vaccine can be administered to leukaemic children in remission.

3. Postpone vaccination
• if the vaccine is suffering from an acute infection or fever (temperature > 38.5°C)

4. Be cautious if there is,
• a bleeding disorder
• a history of Guillain Barre Syndrome
• a progressive neurological disorder

5. Postpone pregnancy
• for three months after varicella vaccination
• for one month after MMR

6. Vaccination should be given in a hospital if there is history of severe allergy.

7. Vaccination should be given only in clinics where the following minimum facilities are available.
Adrenaline, Syringes, Canula, Saline and a Bed. It is preferable to have a complete emergency tray.

Dr Maxie Fernandopulle MBBS, MRCP
Consultant Paediatrician, Colombo.
SLMA guidelines information on vaccines

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The immunisation schedule in UK

The overall aim of the routine immunisation schedule is to provide protection against the following vaccine-preventable infections:

● diphtheria
● tetanus
● pertussis (whooping cough)
● Haemophilus influenzae type b (Hib)
● polio
● meningococcal serogroup C disease (MenC)
● measles
● mumps
● rubella
● pneumococcal disease (certain serotypes)
● human papillomavirus types 16 and 18 (also 6 and 11)
● rotavirus
● influenza
● shingles

The schedule for routine immunisations and instructions for how they should be administered are given in following image. The relevant chapters on each of these vaccine-preventable diseases provide detailed information about the vaccines and the immunisation programmes.

Schedule for the UK’s routine immunisations (excluding catch-up campaigns)

The immunisation schedule of childhood vaccinations has been designed to provide early protection against infections that are most dangerous for the very young. This is particularly important for diseases such as whooping cough, and those due to pneumococcal, Hib and meningococcal serogroup C infection. Providing subsequent immunisations and booster doses as scheduled should ensure continued protection. Further vaccinations are offered at other points throughout life to provide protection against infections before eligible individuals reach an age when they become at increased risk from certain vaccine-preventable diseases.

Recommendations for the age at which vaccines should be administered are informed by the age-specific risk for a disease, the risk of disease complications and the ability to respond to the vaccine. The schedule should therefore be followed as closely as possible.

The first dose of primary immunisations can be given from six weeks of age if required in certain circumstances e.g. travel to an endemic country. A four week interval is recommended between each of the three doses of DTaPcontaining vaccine in the primary schedule although if one of these doses is given up to a week early, either inadvertently or deliberately e.g. for travel reasons, then this can be counted as a valid dose and does not need to be repeated. However, no more than one dose should be given early in the three dose schedule. Similarly for other multiple dose schedule vaccines e.g. HPV, giving subsequent doses at a slightly shorter than recommended interval is unlikely to be highly detrimental to the overall immune response but should be avoided unless necessary to ensure rapid protection or to improve compliance. Every effort should be made to ensure that all children are immunised, even if they are older than the recommended age range; no opportunity to immunise should be missed. A notable exception is the rotavirus vaccine, where the first dose should not be given to babies older than 15 weeks of age and the second dose should not be given if the child is over 24 weeks of age. If any course of immunisation is interrupted, it should be resumed and completed as soon as possible. There is generally no need to start any course of immunisation again, as immunological memory from the priming dose(s) is likely to be maintained. Where vaccination was commenced some time previously, however, the product received may have changed and the relevant chapter should therefore be consulted.

Following immunisation all the patient’s clinical records including the GP held record and, if a child, the record on the Child Health Information System (CHIS) and the Personal Child Health Record (Red Book) should be updated with all the relevant details. When children attend for any vaccination, it is important to also check that they are up-to date for vaccines that they should have received earlier. The table below gives an example checklist at each key stage; doses of the listed vaccines that have not been received by that age should be caught up. Catch-up doses should be administered as soon as possible but leaving the appropriate intervals as advised in the relevant chapters. By these key ages, children’s immunisation status can be checked and, wherever appropriate, they should be offered catch-up vaccinations, to complete their vaccinations, as follows:

By the age of 12 months:

     Three doses of diphtheria, tetanus, polio, pertussis and Hib containing vaccines.
     Two doses of PCV conjugate vaccine.

     One dose of MenC conjugate vaccine.

By the age of 24 months:

     Three doses of diphtheria, tetanus, polio, pertussis containing vaccines.
     A single dose of Hib/MenC and PCV conjugate vaccines after the age of one.
     A single dose of MMR after the age of one.

By school entry:

     Four doses of diphtheria, tetanus, pertussis and polio containing vaccines.
     Two doses of MMR vaccine after the age of one year.
     A single dose of Hib/MenC conjugate after the age of one.

By transfer to secondary school:

     Four doses of diphtheria, tetanus, polio vaccine.
     Two doses of MMR vaccine after the age of one year.
     One dose of MenC containing conjugate vaccine since the age of one year.

Before leaving school:

     Five doses of diphtheria, tetanus, polio vaccine.
     A single dose of MenC after the age of 10 years.
     Two doses of MMR.
     Two doses of HPV vaccine (for girls only)*.

The phased introduction of the influenza vaccine began in 2013 with the inclusion of children aged two and three years in the routine programme. Eventually all children aged 2 to less than 17 years should be offered influenza vaccine annually. Chapter 19 should be consulted for age eligibility. When babies are immunised in special care units, or children and adolescents are immunised opportunistically in accident and emergency units or inpatient facilities, it is most important that a record of the immunisation is entered onto the relevant CHIS and sent to the patient’s GP for entry onto the practice-held patient record by return of an ‘unscheduled immunisation form’. Details should also be recorded in the child’s Personal Child Health Record (Red Book) in a timely manner.

Vaccination of children with unknown or incomplete immunisation status

For a variety of reasons, some children may not have been immunised or their immunisation history may be unknown. If children coming to the UK are not known to have been completely immunised, they should be assumed to be unimmunised and a full course of immunisations should be planned. Where a child born in the UK presents with an inadequate immunisation history, every effort should be made to clarify what immunisations they may have had. A child who has not completed the routine childhood programme should have the outstanding doses as described in the relevant chapters.Children coming to the UK who have a history of completing immunisation in their country of origin may not have been offered protection against all the antigens currently protected against in the UK. For country-specific information, please refer this, Document.  Children coming from developing countries, from areas of conflict or from hard-to-reach population groups may not have been fully immunised. Where there is no reliable history of previous immunisation, it should be assumed that children are unimmunised and the full UK recommendations should be followed.

Children coming to the UK may have had a fourth dose of a diphtheria/ tetanus/ pertussis-containing vaccine that is given at around 18 months in some countries. This dose should be discounted, as it may not provide continued satisfactory protection until the time of the teenage booster. The routine preschool and subsequent boosters should be given according to the UK schedule. Similarly, if a dose of MMR or a measles-containing vaccine is given before the first birthday because of travel to an endemic country, because of a local outbreak, or because it has been given abroad as part of another country’s immunisation schedule, then this dose should be discounted and two further doses given at the recommended times between 12 and 13 months of age (i.e. within a month of the first birthday) and at three years four months or soon after. An algorithm for vaccinating individuals with uncertain or incomplete immunisation status is available at Document.

Premature infants

It is important that premature infants have their immunisations at the appropriate chronological age, according to the schedule. The occurrence of apnoea following vaccination is especially increased in infants who were born very prematurely. Very premature infants (born ≤ 28 weeks of gestation) who are in hospital should have respiratory monitoring for 48-72 hrs when given their first immunisation, particularly those with a previous history of respiratory immaturity. If the child has apnoea, bradycardia or desaturations after the first immunisation, the second immunisation should also be given in hospital, with respiratory monitoring for 48-72 hrs (Pfister et al., 2004; Ohlsson et al., 2004; Schulzke et al., 2005; Pourcyrous et al., 2007; Klein et al., 2008). As the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delayed.

Selective childhood immunisation programmes

There are a number of selective childhood immunisation programmes that target children at particular risk of certain diseases, such as hepatitis B, tuberculosis, influenza, meningococcal and pneumococcal infection. For more information please see the relevant chapters.

Adult immunisation programme 

Five doses of diphtheria, tetanus and polio vaccines ensure long-term protection through adulthood. Individuals who have not completed the five doses should have their remaining doses at the appropriate interval. Where there is an unclear history of vaccination, adults should be assumed to be unimmunised. A full course of diphtheria, tetanus and polio vaccine should be offered in line with advice contained in the relevant chapters. Selective vaccines against diseases including measles, mumps and rubella should be offered to young adults who have not received routine childhood immunisations. In addition, MenC should be considered in those under 25 years who are unvaccinated and for younger cohorts where the routine adolescent dose has been missed (see Chapter 22). Other vaccinations should be considered for any adult with underlying medical conditions and those at higher risk because of their lifestyle. These vaccinations include Hib, MenB, MenC, MenACWY, influenza, pneumococcal and hepatitis B. For more information please see the relevant chapters. Older adults (65 years or older) should be routinely offered a single dose of pneumococcal polysaccharide vaccine, if they have not previously received it. Annual influenza vaccination should also be offered. Adults aged 70 years should also be offered shingles vaccine.

Vaccination in pregnancy

A temporary programme for the vaccination of pregnant women against pertussis was introduced in October 2012. The purpose of the programme is to boost antibodies in these women so that they are passed from mother to baby. This should protect the infant against pertussis infection from birth until they are vaccinated at two months of age. Pregnant women should be offered dTaP/IPV vaccine in weeks 28-38 of their pregnancy (ideally in weeks 28-32), for each pregnancy. Pertussis vaccine can be given at the same time as influenza vaccine but pertussis vaccination should not be given early in order to offer the vaccines at the same time as this will compromise the passive protection to the infant. This temporary programme is described in more detail in the following documents: (Document 1, Document 2)

In 2010, routine influenza immunisation of certain clinical risk categories was extended to include pregnancy. This was based on evidence of the increased risk from influenza to the mother and because vaccination during pregnancy will provide passive immunity against influenza to infants in the first few months of life following birth. Protection of the mother should also reduce the risk of her transmitting infection to a newborn baby. Inactivated influenza vaccine should therefore be offered to pregnant women at any stage of pregnancy (first, second or third trimesters), ideally before influenza viruses start to circulate. Influenza vaccination is usually carried out between October and January, however clinical judgement should be used to assess whether a pregnant woman should be vaccinated after this period, taking into account factors including the level and severity of influenza-like illness in the community and the availability of inactivated influenza vaccine. Influenza vaccine can be given at the same time as pertussis vaccine but influenza vaccination should not be delayed in order to offer the vaccines at the same time. Inactivated influenza vaccines are preferred to live attenuated vaccines for pregnant women.

References -

Klein NP, Massolo ML, Greene J et al. (2008) Risk factors for developing apnea after immunization in the neonatal intensive care unit. Pediatrics 121(3): 463-9.

Miller E, Andrews N, Waight P et al. (2011). Safety and immunogenicity of coadministering a combined meningococcal serogroup C and Haemophilus influenzae type b conjugate vaccine with 7-valent pneumococcal conjugate vaccine and measles, mumps, and rubella vaccine at 12 months of age. Clin Vaccine Immunol 18(3): 367-72.

Ohlsson A and Lacy JB (2004) Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. Cochrane Database Syst Rev (1): CD000361. Pfister RE, Aeschbach V, Niksic-Stuber V et al. (2004) Safety of DTaP-based combined immunization in very-low-birth-weight premature infants: frequent but mostly benign cardiorespiratory events. J Pediatr 145(1): 58-66.

Pourcyrous M, Korones SB, Arheart KL et al. (2007) Primary immunization of premature infants with gestational age protein responses associated with administration of single and multiple separate vaccines simultaneously. J Pediatr 151(2): 167-72.

Schulzke S, Heininger U, Lucking-Famira M et al. (2005) Apnoea and bradycardia in preterm infants following immunisation with pentavalent or hexavalent vaccines. Eur J Pediatr 164(7): 432-5.

Original Article Source - www.gov.uk

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National Immunization Programme of Sri Lanka and Key Principles in Immunization

In the year 1798, Edward Jenner first demonstrated that vaccination offered protection against smallpox. He used cowpox (poxvirus bovis) for the immunization of man against the smallpox virus (poxvirus varialae). For the last 200 years, the use of vaccines has continued to reduce the burden of many bacterial and viral diseases.

Smallpox itself has been eradicated, and poliomyelitis in the verge of eradication. In Sri Lanka, the last case of virologically confirmed poliomyelitis patient was reported in 1993.

In Sri Lanka, the introduction of routine immunization has generally reduced the incidence of several vaccine preventable diseases. Similar success in disease reduction has been demonstrated by immunization programmes in many other countries. The World Health Organization’s (WHO) Expanded Programme on Immunization (EPI), with assistance from the United Nation’s Children’s Fund (UNICEF) and other donors, has made great strides in extending these benefits to developing countries. Immunizations permitted the global eradication of smallpox, and may do the same for poliomyelitis and some other diseases.

Immunizing a child not only protects that child but also other children by increasing the general level of immunity and minimising the spread of infection.

History of Immunization in Sri Lanka

The history of immunization in Sri Lanka goes back to the 19th century. The law relating to compulsory vaccination (against smallpox) is referred to in the Vaccination Ordinance of 1886.

The Expanded Programme on Immunization (EPI) established in 1978, has continued to make excellent progress over the past two decades, most notably in terms of achieving high immunization coverage and disease control. The milestones of immunization in Sri Lanka are given below.

1886 - Vaccination against smallpox introduced under the Vaccination Ordinance
1949 - BCG Vaccination introduced against tuberculosis
1961 - “Triple” vaccination introduced against diphtheria, whooping cough and tetanus
1962 - Oral polio vaccine introduced
1963 - BCG vaccination of newborn introduced
1969 - Tetanus Toxoid administration to pregnant mothers introduced
1978 - Launching of the Expanded Programme on Immunization
1984 - Measles vaccination introduced

1991 - Revision of Tetanus Toxoid schedule
1995 - First National Immunization Days conducted.
1996 - Introduction of Rubella vaccine
2001 - Introduction of revised National Immunization Schedule with MR and ATd
2003 - Introduction of Hepatitis B Vaccine on phase basis
2008 - Introduction of Hib containing Pentavalent vaccine

Immunization Schedule

With the commencement of the EPI Programme in 1978 focus was to control childhood T.B., tetanus, whooping cough, diphtheria, polio and neo-natal tetanus. In 1988, the focus shifted to disease elimination. In 1991, a fifth dose of OPV was introduced at school entry to facilitate the polio eradication process. Rubella, Hepatitis B and Hib containing Pentavalent vaccines introduced to the programme gradually over the years. The present EPI vaccination schedule is given in annex below. JE vaccine was introduced to high-risk areas in 1987. Primary Immunization against JE consists of 3 doses at an interval of 2 – 4 weeks between the first and second doses and one year between the second and third. A booster dose is given every 4 years after the primary immunization. JE immunization is offered children below the age of ten years living in identified high-risk areas.

Principles for Determination of Immunization Schedule

• Age specific risk of disease
• Age specific immunological response to vaccines
• Potential interference with the immune response by passively transferred material antibody
• Age specific risk of vaccine associated complications
• Programmatic feasibility
• In general vaccines should be administered to the youngest age group at riks for developing the disease

 Objectives of the National Immunization Programme

• Eradication of poliomyelitis  Elimination of neonatal tetanus, diphtheria, measles and rubella
• Reduction of morbidity and mortality due to whooping cough prevention of outbreaks
• Reduction of morbidity and mortality due to hepatitis B
• Reduction of morbidity and mortality due to Japanese Encephalitis
• Reduction of morbidity and mortality due to Haemophilias influence B disease

To achieve the above objectives, immunity has to be create in population against the specific organisms causing above diseases by administering potent vaccines in correct dosage using correct technique and according to the national immunization schedule.

‘Immunity’ is a term that originally implied exemption from military service or taxes; it was introduced into medicine to refer to those people who did not get further attacks of smallpox or plague once they had had the disease. In a wide sense the term refers to the resistance of a host organism to invasive pathogens or their toxic products. Immunity is divided into two main types

Non-specific immunity (sometimes called ‘innate immunity’): which includes the general protective reaction of the organism against invasion.

Specific immunity: Immunity is the ability of the body to tolerate material that is indigenous to it and eliminate material that is foreign. The immune system is comprised of organs and specialized cells that protect the body by identifying harmful substances, known as antigens, and by destroying them by using antibodies and other specialized substances and cells. There are two basic ways to acquire this protection – active immunity and passive immunity.

Passive immunity: involves either the transfer of antibodies or in some diseases, of sensitised white blood cells, from an immune to a non-immune person. Natural passive immunity is transferred from mother to child across the placenta (and in the colostrum in subhuman primate species). Artificial transfer is the therapeutic use of various antitoxins or gammaglobulins, as in the treatment of tetanus, diphtheria, gas gangrene, snakebite, and immunodeficiency states. The passive immunity is short-lived, depending on the life-span of the antibody or the transferred cells in the recipient. Once they disappear, the host is again susceptible to the disease.

Active immunity: is provided by a person’s own immune system. This type of immunity can come from exposure to a disease or from vaccination. Active immunity usually lasts for many years and often is permanent. Live microorganisms or antigens bring about the most effective immune responses, but an antigen does not need to be alive for the body to respond.

Types of Vaccine

Live attenuated vaccines are derived from disease-causing viruses or bacteria that have been weakened under laboratory conditions. They will grow in a vaccinated individual, but because they are weak, they will cause either no disease or only a mild form. Usually, only one dose of this type of vaccine provides life-long immunity, with the exception of oral polio vaccine, which requires multiple doses.

Inactivated vaccines are produced by growing viruses or bacteria and then inactivating them with heat or chemicals. Because they are not alive, they cannot grow in a vaccinated individual and therefore cannot cause the disease. They are not as effective as live vaccines, and multiple doses are required for full protection. Booster doses are needed to maintain immunity because protection by these vaccines diminishes over time.

Inactivated vaccines may be whole-cell or fractional. Whole-cell vaccines are made of an entire bacterial or viral cell. Fractional vaccines, composed of only part of a cell, are either protein- or polysaccharide-based. Polysaccharide-based vaccines are composed of long chains of sugar molecules taken from the surface capsule of the bacteria. Unless coupled with a protein, pure polysaccharide vaccines are generally not effective in children under the age of two years. This coupling process is known as “conjugation.” Recombinant vaccines are produced by inserting genetic material from a disease-causing organism into a harmless cell, which replicates the proteins of the disease-causing organism. The proteins are then purified and used as vaccine.

Types of Vaccine,

• Live attenuated
– Virus, e.g., oral polio vaccine (OPV), measles, yellow fever
– Bacteria, e.g., BCG

• Inactivated

Whole
– Virus, e.g., inactivated polio vaccine (IPV)
– Bacteria, e.g., whole-cell pertussis

Fractional

– Protein-based
– Subunit, e.g., acellular pertussis
– Toxoid, e.g., diphtheria and tetanus
– Polysaccharide-based
– Pure, e.g. meningococcal
– Conjugate, e.g., Haemophilus influenzae type b (Hib)


• Recombinant, 

-Hepatitis B

Impact of Immunization on Disease Transmission

An infectious disease is an illness that occurs when an infectious agent is transmitted from an infected person, animal, or reservoir to a susceptible host. Some of the factors that influence transmission include:

A basic concept of public health is that every individual who is protected from a disease as a result of an immunization is one less individual capable of transmitting the disease to others. Individuals who have been immunized serve as a protective barrier for other individuals who have not been immunized, provided that the number immunized has reached a certain level. Reaching and maintaining that level, which varies by communicable disease, provides “herd immunity” to unimmunized individuals. The figure bellow illustrates the concept of herd immunity. It shows two hypothetical populations in which each individual comes in contact with four other members of the population. Both populations have been exposed to a hypothetical disease that is 100% contagious. The first group has no immunity to the disease and, therefore, the disease spreads to everyone. The second population is partially immune due to vaccination services that have protected 75% of the population. Even though only 75% are immune because of vaccination, the disease does not spread to all of the remaining 25% of susceptible individuals. This is because some of the remaining susceptible are protected by the fact that they do not come in contact with an infected individual. This is how herd immunity can protect more people than those who actually receive vaccinations and thus inhibit the spread of disease.

Note that if the susceptible individuals are unevenly distributed, e.g., if they cluster in urban slums, the level of protection in that population will need to be higher to prevent transmission. However, immunization coverage is not near 100 % these unimmune persons (susceptible) can accumulate over the years and can cause outbreaks as experienced in 1999 measles outbreak. Therefore, it is important to plan and organize our immunization programme in such a way that minimum susceptible accumulate over the years.

Click here to download Immunization Schedule

Source - http://www.epid.gov.lk

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