C. Mhorag Hay VACCINATION What you need to know: 1. The nature and function of passive and active immunization 2. The role of humoral and cellular immunity in vaccination 3. The types of vaccines currently available and the pros and cons of their use Introduction: Vaccination, or immunization, is the act of artificially inducing immunity from disease. Its use dates back to 1796 when Jenner showed that inoculating vesicular fluid from cowpox lesions into the skin of susceptible individuals could protect them against smallpox infection. A modified cowpox virus known as vaccinia virus is currently used to protect against smallpox and it is from this that we get the term vaccination. Passive versus Active Immunization: Passive immunization consists of providing temporary protection from disease through the administration of exogenously produced antibody. Infants are passively immunized from their mothers through transplacental transfer of maternal antibodies. These antibodies protect the infant for 3-6 months after birth and allow the infant s own immune system time to develop. Pooled human IgG, known as immunoglobulin, is used for passive immunization against hepatitis A and measles. Passive immunization against these diseases is used after a non-immune person has been exposed to the infection but before they develop the disease in an attempt to avoid serious illness. Pooled immunoglobulin is also used to prevent infection in individuals with immune deficiencies such as X-linked agammaglobulinemia. Special preparations of immunoglobulin taken from donor pools with high levels of antibodies specific to certain infectious agents are also used to passively protect individuals from infections. - Hepatitis B immune globulin is used to protect neonates born to hepatitis B carrying women and to protect non-immune persons after exposure to HBV. - Varicella zoster immune globulin (VZIG) is used to prevent serious chickenpox infections in exposed, non-immune individuals at high risk of severe infection. - Rabies immune globulin is used to protect people exposed to rabies infection during the time it takes for immunity to be built up by active immunization. - RSV immune globulin (RSVIG) is used to protect premature infants and infants with lung disease from serious RSV infection - Tetanus immune globulin (TIG) is used to prevent tetanus infections in unimmunized, exposed individuals
Antibodies provided by passive immunization are generally short-lived and do not give the long-lasting protection of active immunization strategies. Active immunization consists of inducing the body to develop defenses against disease. This usually is accomplished by giving agents that stimulate the body s immune system to produce antibodies and/or cell mediated immune responses against a particular infectious agent. This is the form of immunization that we usually think of when we talk about vaccination and the various agents of active immunization will be covered in detail in the following sections. The immune system in active immunization: Antibodies react with antigens in the blood stream and extracellular fluid and at mucosal surfaces. They cannot readily reach intracellular sites of infection. Most antibodies produced by vaccines are thymus-dependent in that they require activation of T helper cells to initiate B cell proliferation and antibody production. After an antigen, in this case a vaccine component, enters the body it is presented by mononuclear phagocytes or dendritic cells which trigger a cascade of cytokines and stimulate the maturation of naïve T helper cells into T helper type 2 cells (T H 2). T H 2 cells in turn produce cytokines that lead to maturation of naïve B cells and release of specific antibody. After the initial immune response is induced by the vaccine, activated B cells become resting memory cells ready to respond rapidly when the antigen is encountered again. Protective antibodies against bacterial infections work in several different ways depending on the type of pathogen encountered. They can: 1. Inactivate soluble toxic products (anti-toxins, e.g. diphtheria vaccine) 2. Facilitate phagocytosis of bacteria (e.g. pneumococcal vaccine) 3. Interact with serum complement to damage bacterial membranes and facilitate bacteriolysis (typhoid vaccine) and/or 4. Interfere with the bacterium s ability to adhere to mucosal surfaces. Protective antibodies against viral infections can only work when the virus is in extracellular spaces. These antibodies may bind to viruses preventing their entry into cells or may interfere with uncoating of virus particles or other steps in the viral lifecycle. Cell mediated immunity is directed against intracellular antigens and thus is most effective against organisms that spend at least part of their lifecycle inside cells. Cytotoxic T cells (CTL) recognize small fragments of antigens presented on the surface of infected cells in combination with HLA class I molecules. The T cell receptor molecules of CTL are designed to recognize a specific antigen in combination with a specific HLA molecule. Like thymus dependent antibody production, the induction of cellular immunity is dependent upon the activation of T helper cells; however, in order to stimulate cell mediated immunity, T helper cells mature along the T helper type 1 (T H 1) pathway. T H 1 cells release cytokines that cause the maturation of naïve cytotoxic T cells which can then recognize intracellular antigens using their T cell receptors. When the T cell receptor of the mature CTL recognizes its antigen combined with its HLA class I molecule on the surface of an infected cell it releases substances that kill the infected cell. Like antibody producing B cells, CTL can become resting memory cells ready to become activated as soon as the host is exposed to the antigen again. 2
On first exposure to a vaccine antigen, the primary response requires a latent period of several days before humoral (antibody) and cell mediated immunity can be detected. Circulating antibodies do not appear for 7-10 days and initially are of the IgM class. Two or more weeks after vaccination the titers of IgG antibodies rise. After a second exposure to the same antigen heightened antibody and cell mediated immune responses are seen and occur within 4-5 days after exposure. Because antibody responses are easier to measure, the response to a vaccine is usually measured by the antibody titer in the serum of the vaccinated host; however, cell mediated immune responses have been shown to be induced by vaccines and the lack of detectable antibody does not mean that the individual is necessarily unprotected by the vaccine. Determinants of the Effectiveness of Active Immunization: The ability of a vaccine to produce an effective immune response is determined by the vaccine antigen(s), the genetic background of the vaccinee (e.g. HLA type), the physiologic condition of the vaccinee, the manner in which the vaccine antigen is presented, dose, use of adjuvants and route of administration. HLA types vary widely amongst individuals and contribute the recognition of different parts of a complex antigen in different populations. This variation is of particular importance for vaccines that primarily attempt to elicit cell mediated immunity (e.g. HIV vaccine). These vaccines must contain antigenic molecules that can be recognized and presented by at least one HLA molecule in every individual vaccinated. Differences in HLA types may explain why certain people never respond to certain vaccines (hepatitis B vaccine). The age, nutritional status, and immune status of a vaccinee may influence the effectiveness of the response to a vaccine. Young infants often do not respond to vaccines because of the presence of maternal antibodies. The elderly often have diminished immune responses to vaccines because of waning cellular immunity. Severely malnourished individuals have blunted immune responses and people with immune deficiencies may be unable to respond to many vaccines. The type of vaccine used may have significant effects on immunogenicity. Live attenuated vaccines, in which a weakened strain of live infectious agent is given to the vaccinee (measles, mumps, rubella), actually multiply in the recipient until checked by the immune response. Most of these vaccines can confer life-long immunity after a single dose because they allow for large amounts of antigen to be presented to the immune system. Killed or subunit (vaccines containing only part of the infecting organism) vaccines in contrast usually require more than a single dose and often require booster shots (tetanus, rabies, diphtheria) throughout life. The dose and route of administration of the vaccine can also affect immunogenicity. There is usually a dose-response curve relationship between antigen dose and peak response; however, this response often plateaus. The route of administration may determine the nature of the immune response to a vaccine. Intranasally administered vaccines are more likely to induce local IgA production than parenterally administered vaccines. Adjuvants are substances added to vaccines that enhance the immunogenicity of antigens. They are particularly useful with inactivated vaccines and toxoids. The mechanism of immune enhancement is not completely defined but may include mobilization of phagocytes and delayed release of antigen. 3
Currently Available Vaccines Recommended for General Use: Currently available vaccines can be made up of live attenuated organisms, whole killed organisms, fractions of organisms or toxoids (modified bacterial toxins which are nontoxic but retain immunogenicity). Live attenuated vaccines consist of live organisms that have been specially modified to make them considerably less virulent than wild type pathogens. These vaccines have the ability to infect the vaccinated host and multiply, but generally do not cause disease. For the reasons given earlier, they are generally the most effective vaccines available; however, because they do contain live organisms their use may be problematic in certain populations (e.g. pregnant women, people with AIDS, etc) and not every organism can be attenuated enough that it does not cause disease but remains capable of inducing an immune response (e.g. HIV to date). Measles vaccine is a live attenuated virus vaccine with an efficacy of over 95% when administered in a single dose to children over the age of 15 months; however, because measles can continue to circulate in the 2-5% of the population who do not respond, 2 doses of vaccine are recommended (second dose generally at school entry). The introduction of the measles vaccine in the US has resulted in 99.75% decrease in measles cases; however, vaccination rates may be quite low in developing countries. Travelers should be adequately vaccinated as a recent outbreak of measles in Queens in US born infants who had traveled to India before being vaccinated illustrates. Mumps vaccine is also a highly effective live attenuated vaccine recommended for all children over the age of one who do not have specific contraindications (immunocompromise). Protection is lifelong after a single dose although most people receive two doses as part of the MMR vaccine. The mumps vaccine has led to a 98.3% decline in mumps cases in the US since 1968. Rubella vaccine is a live attenuated vaccine which makes up the third component of the MMR vaccine. Its purpose is to prevent the congenital rubella syndrome by ensuring that all women of childbearing age are protected against infection. A single dose confers lifelong protection in 95% of vaccinees. Because the live attenuated rubella virus can cross the placenta this vaccine is contraindicated in all pregnant women and within three months of a planned conception. However, data on 226 women who received rubella vaccine during pregnancy or within three months of conception showed no evidence of congenital rubella syndrome. Oral polio vaccine is a live attenuated vaccine given in three doses to children at 2, 4, and 6 months of age. It is highly effective and easy to administer; however, because live polio virus is secreted from the intestines of vaccinated individuals for a short time after vaccination and because vaccine polio virus can cause paralytic disease this form is no longer used in this country where polio has been eradicated. Oral polio vaccine is still the vaccine of choice of the World Health Organization s effort to eradicate polio from the world. Varicella zoster vaccine was approved in 1995 for use in the United States. It is given at 12-18 months of age and is highly effective in preventing severe varicella infections. Its use is also recommended for adults who may be exposed to VZV and who are not immune (health care workers, daycare attendants, etc). This vaccine was originally developed for immunocompromised children; however, because it can cause chickenpox-like symptoms it is currently contraindicated in individuals with severe immunodeficiency. The vaccine can cause a mild chickenpox rash in immunocompetent hosts and has been shown to go latent in dorsal ganglion cells with subsequent reactivation zoster; however, it is felt that the risk of zoster in vaccinated individuals is less than that in naturally infected individuals. 4
Whole killed vaccines consist of organisms that have been inactivated so that they are no longer capable of infecting a host or of multiplying within the vaccinated host. These vaccines do not cause disease but can elicit an immune response. However, because they do not replicate in the vaccinee they provide less antigenic stimulus than live attenuated vaccines and often require multiple doses to ensure protection. For the most part, these vaccines are safe and can be used in immunocompromised individuals. Adverse reactions to whole killed vaccines are often seen in children. Hepatitis A vaccine is derived from formalin inactivation of hepatitis A virus and is recommended for travelers to areas of the world where hepatitis A is endemic and for children in communities with high rates of hepatitis A (and there are a lot!). The vaccine is very effective at least in the short term. Two doses given 6-12 months apart appear to be protective for at least 10 years. Longer term protection may require further boosting. Influenza virus vaccine is composed of whole or disrupted (split) influenza viruses. The viruses chosen change from flu season to flu season depending upon which strains are likely to circulate. Revaccination is recommended yearly as strains change and antibody levels decline over a 6-9 month period after vaccination. Efficacy of this vaccine is 60-80% in healthy adults. It is less in elderly and immunocompromised individuals; however, the vaccine is still effective in this group at preventing serious illness, hospitalization and death. A live attenuated nasal influenza vaccine (Flumist) recently received FDA approval for healthy individuals aged 5-49. Pertussis vaccines come in two different preparations in this country. The first to be introduced was the whole cell vaccine which consists of whole killed Bordetella pertussis. More recently an acellular preparation has become available which consists of combinations of purified components of the organism and detoxified pertussis toxin. Whole cell pertussis vaccines are associated with a higher rate of adverse events after vaccination than are most other vaccines in common use. In a large prospective study more than 60% of vaccinees had local reactions or fever after receiving the vaccine. Febrile convulsions (without sequelae) were seen in 1/1750 vaccinees. Acellular pertussis vaccine causes fewer local and systemic reactions than the whole virus vaccine and for this reason is now the favored form of vaccination. Pertussis vaccine is usually combined with diphtheria and tetanus vaccines to produce the DTP (now DTaP as the acellular preparation is used) given to infants at 2, 4, 6, and 15-18 months with a booster at school entry age. Inactivated polio vaccine is currently the polio vaccine of choice in the United States. It is prepared by formalin inactivation of poliovirus strains and has been formulated to contain antigens recognized by 99% of the population (enhanced potency IPV). This vaccine is more immunogenic than OPV but must be administered parenterally (subcutaneously). It is given on the same schedule as OPV (2, 4, 6-18 months) and has an excellent safety record. Vaccination against polio has resulted in the eradication of wild-type polio infection from the Western hemisphere and from Europe. Subunit vaccines consist of immunogenic parts of whole organisms and are used when attenuation of the organism is difficult and whole killed vaccines are either not immunogenic enough or too toxic. Many subunit vaccines are conjugated, that is attached to protein carriers which greatly enhance their immunogenicity. Subunit vaccines, like killed vaccines, cannot cause disease. In general, adverse events are rare with subunit vaccines. Haemophilus b vaccine consists of purified high molecular weight haemophilus b polysaccharide (PRP) which is covalently linked to a carrier protein. The linkage of the polysaccharide to the carrier protein greatly enhances the immunogenicity of the vaccine 5
and allows for its use in young infants (the group most at risk of serious Hib infection). There are currently 4 licensed formulations of the vaccine which differ in their carrier protein. PRP-D, which consists of the PRP linked to diphtheria toxoid, is the least immunogenic of the 4 and is not recommended for use in infants. PRP-OMC, which consists of the PRP linked to the outer membrane protein complex derived from N. meningitidis, is the most immunogenic formulation. PRP-T (PRP linked to tetanus toxoid) and HbOC (oligosaccharide linked to mutant diphtheria toxin protein) are as effective as PRP-OMC but require an extra dose of vaccine at 6 months. Hib vaccine is generally given at 2 and 4 months of age with a boost at 12-15 months if using the PRP- OMC preparation. If using PRP-T or HbOC a third dose at 6 months followed by a boost at 12-15 months is recommended. All preparations of the vaccine are quite safe and have resulted in a dramatic decrease in serious Hib infections in vaccinated populations. Hepatitis B vaccine consists of purified, inactivated hepatitis B surface antigen particles derived, nowadays, from recombinant DNA technology. In some other countries HBV vaccine is still made from HBsAg particles derived from the plasma of chronic carriers of HBV. The vaccine is safe, well-tolerated and generally highly effective although a small number of vaccinated individuals never seroconvert. Vaccination is currently recommended for all adults with potential blood/ body fluid exposure (that includes all of you) and is given to all infants in the United States (usually in combination with a Hib vaccine). Meningococccal polysaccharide vaccine contains purified meningococcal polysaccharides of groups A, C, Y, and W135. A single IM dose induces protective antibody levels in over 90% of vaccinees over the age of 2. Adverse events are rare. The vaccine is recommended for high risk groups including those with complement deficiency, asplenia, and travelers to countries with endemic disease. It is recommended by some for college students, particularly freshmen living in dormitory accommodation. It should be noted that the vaccine does not confer protection against group B meningococcus infection -- an important cause of meningitis. Both pneumococcal polysaccharide vaccine and conjugated pneumococcal polysaccharide vaccine are currently available in the United States. The unconjugated vaccine consists of 23 different serotypes of pneumococcal capsular polysaccharide covering the strains responsible for 85% of all bacteremic pneumococcal disease in the US. This vaccine is recommended for people over the age of 65 and in adults and children over the age of 2 with high risk for pneumococcal disease. The conjugated pneumococcal polysaccharide vaccine consists of polysaccharide from 7 serotypes of pneumococcus linked to protein carriers. It is recommended for all children aged 2-23 months and is generally given at 2,4,6, and 12-15 months. Toxoids are modified bacterial toxins that have been rendered non-toxic but retain the ability to stimulate the formation of antibodies (antitoxins). Toxoids are generally safe and well-tolerated but most do not produce life-long immunity and require booster doses. Diphtheria toxoid is a purified preparation of inactivated diphtheria toxin. It is highly effective in inducing antibodies that will prevent disease although it has little effect on acquisition or carriage of the actual organism, Corynebacterium diphtheriae, that makes the toxin. Local reactions to the toxoid are frequent especially with booster doses. A high dose of toxoid is given in combination with pertussis vaccine and tetanus toxoid to young children (DTaP) and in a lower dose in combination with tetanus toxoid (Td) to older children and adults. After the initial 3 doses of toxoid, booster doses need to be given every 10 years to ensure continued protection against diphtheria. The use of the diphtheria toxoid has resulted in a 99.99% decrease in cases of diphtheria in the United States from 1921 to 1992. 6
Tetanus toxoid is a purified preparation of inactivated tetanus toxin precipitated with alum and is one of the most effective immunizing agents known. A course of 3 doses induces protective antibodies in over 95% of recipients. It is given to young children as part of the DTaP vaccine and to older children and adults as the Td vaccine. After the initial series of vaccinations boosters are recommended every 10 years (given as Td to ensure both tetanus and diphtheria protection is given). The most common side effects are fever and local reactions. As the local reactions can be quite severe, boosters are recommended only every 10 years unless a particularly tetanus-prone wound has occurred in which case a booster should be given if it is more than 5 years since the last booster. Tetanus cases have decreased over 97% since the introduction of tetanus toxoid. Other Vaccines to Know About: A number of other vaccines are available and recommended for use under certain circumstances. It is worthwhile knowing about these vaccines especially if you work with travelers and immigrants, plan to travel yourself, or have an interest in potential agents of bioterrorism. Anthrax vaccine is a cell-free filtrate prepared from microaerophilic cultures of an avirulent strain of Bacillus anthracis. The vaccine is indicated only for those at high risk of anthrax infection (this definition may change over time but currently consists of people coming into contact with animal hides from endemic areas, laboratory personnel working with anthrax, and the military). Its efficacy is not known but it does induce antibodies in over 90% of individuals who receive the primary course of 6 subcutaneous injections. Annual boosting is required to sustain antibody levels. Mild local reactions are quite common however system reactions are very rare. BCG vaccine contains living Calmette-Guerin bacillus, an attenuated strain of Mycobacterium bovis. Although widely used throughout the world it is not recommended for general use in the United States because it can affect the PPD test and is of controversial efficacy. It appears to be most effective in preventing complications of disseminated TB in young children and it is therefore recommended primarily for infants and young children at high risk of exposure to TB in the US. Because BCG vaccine contains live organisms, it can disseminate in immunocompromised individuals and therefore it should not be used in this population. BCG produces a vigorous local immune response and has been instilled into the bladder to produce an immune response in people with bladder cancer. Rabies vaccine is an inactivated virus vaccine prepared in human or fetal rhesus lung diploid cell culture. The human diploid cell preparation (HDCV) can be used either intramuscularly or intradermally, while the rhesus lung preparation (RVA) can only be used IM. Rabies vaccine is used in people likely to be exposed to rabies (veterinarians, certain travelers, etc) or in people who have been exposed to potentially rabid animals. Preexposure prophylaxis is given as three doses either IM or intradermally at 0, 7, 21-28 days with follow-up boosting every 2 years or when a potential exposure has occurred. Postexposure prophylaxis is given as 5 IM shots on days 0, 3, 7, 14, and 28 along with rabies immune globulin on day 0. Rabies immune globulin is not needed in persons who have received pre-exposure prophylaxis. Local reactions are common (30-74% of vaccinees) and systemic complaints are also frequently seen with rabies vaccine but no contraindication exists for its administration to at risk or exposed individuals (remember the alternative is certain death). Yellow fever vaccine is a live attenuated virus preparation. It is highly effective and very well tolerated and excellent immunity is achieved after a single dose of vaccine. It is recommended for travelers to areas of endemnicity and is required by some countries for entry. As it is a live attenuated virus its use is contraindicated in 7
immunocompromised individuals; although pregnancy is not an absolute contraindication for its use. Smallpox vaccine has resulted in the eradication of naturally occurring smallpox infection on earth. Smallpox vaccines are derivatives of cowpox (vaccinia) virus and are the derivatives of one of three strains: Elstree (Lister, France) strain, EM63 (Moscow) strain, and the New York City Board of Health strain. Smallpox vaccines are produced from a seed virus propagated on the skin of calves and then processed to eliminate bacterial contamination. Vaccinations are given over the deltoid region of the upper arm using a bifurcated needle dipped in the vaccine. The needle is held perpendicular to the skin and pressed in and out 5 times in unvaccinated individuals, 15 times in previously vaccinated individuals. A successful vaccination is defined as a pustular lesion or an area of definite induration or congestion surrounding a central lesion 6-8 days after vaccination. Although smallpox vaccine is highly effective, it does have a number of serious adverse consequences which preclude its general use at the current time. The most frequent complications include: vaccinia necrosum: an often lethal complication of inadvertent vaccination of an immunocompromised host which consists of the insidious progression of an initially normal appearing vaccination with the development of metastatic lesions throughout the body eczema vaccinatum: the consequence of local spread and/or dissemination of vaccinia virus infection in individuals with atopic dermatitis generalized vaccinia: a nonspecific term used to describe a vesicular rash that develops after vaccination. Unlike actual generalized infection such as is seen in vaccinia necrosum or eczema vaccinatum, these reactions can be seen in normal hosts, are generally not accompanied by systemic symptoms, and do not yield virus on culture of the lesions erythematous urticarial eruptions: erythematous rashes observed in otherwise healthy individuals 7-12 days after vaccination. Postinfectious encephalitis is one of the most serious complications of vaccination in normal hosts with a mortality of 10-30%. It occurs in 1/100,000 primary vaccinees. Myocarditis: since the reactivation of smallpox vaccination in military personnel and selected civilian populations, myocarditis, pericarditis and myopericarditis have been reported. Persons with preexisting heart disease are currently advised not to be vaccinated. Sources for Information on Vaccines: Vaccine recommendations do change quite frequently and it is important to know where to go to get the latest updates. In the US, the Advisory Committee on Immunization Practices (ACIP) is responsible for making vaccination recommendations. Their web-page, http://www.cdc.gov/nip/acip/default.htm, includes updated schedules as well as information on how to administer vaccines (where to administer, which ones can be given together), adverse events, and information on individual vaccines. The CDC s web page, www.cdc.gov, includes information on vaccination for travelers, and the WHO, http://www.who.int/en/, lists travel advice and world-wide vaccination effort updates. 8
Baseline 20 th Century Annual Morbidity and 1998 Provisional Morbidity from Nine Diseases with Vaccines Recommended before 1990 for Universal Use in Children-United States Baseline 1998 Disease Morbidity Morbidity % Decrease Smallpox 48,164 0 100% Diphtheria 175,885 1 100% Pertussis 147,271 6279 95.7% Tetanus 1314 34 97.4% Poliomyelitis 16,316 0 100% Measles 503,282 89 99.9% Mumps 152,209 606 99.6% Congenital Rubella 823 5 99.4% H. influenza type b 20,000 54 99.7% Adapted from MMWR 1999;48 (12)245. 9
Vaccines Currently Available Disease Vaccine Type Who should receive vaccine Diphtheria Toxoid Children and adults Tetanus Toxoid Children and adults Pertussis Killed whole cell Not recommended in US Acellular Children H. influenza type b Capsular polysaccharide- Children protein conjugate Meningococcus A,C,Y,W135 Capsular polysaccharide Asplenic patients, military personnel, college freshmen, travelers to endemic areas Asplenic patients, elderly, chronic lung disease Infants Pneumococcus Capsular polysaccharide (23 serovars) Capsular polysaccharideprotein conjugate (7 serovars) Anthrax Cell-free filtrate Military personnel, imported fur handlers Tuberculosis Live attenuated- BCG Not recommended in US Polio Inactivated (IPV) Children, unvaccinated adults traveling to endemic areas Live attenuated (OPV) Not recommended in US Measles Live attenuated Children, non-immune adults Mumps Live attenuated Children, non-immune adults Rubella Live attenuated Children, non-immune adults Chickenpox Live attenuated Children, non-immune adults at risk (healthcare workers, daycare attendants) Influenza Inactivated Adults over 55, at risk populations, healthcare Live attenuated Healthy aged 5-49 Hepatitis B Subunit Infants, high risk adultshealthcare workers, sex workers, IVDU Hepatitis A Inactivated Adults and children in endemic areas Yellow fever Live attenuated Travelers to endemic areas Rabies Inactivated Pre-exposure- travelers, veterinarians Post-exposure- anyone exposed Smallpox Live attenuated Military personnel, selected first responders 10
Combination Vaccines Currently Available Vaccine MMR Components Measles, Mumps, Rubella DTaP Diphtheria, Tetanus, acellular Pertussis Td Pediarix Comvax TriHIBit Twinrix Tetanus, low dose diphtheria DTaP, Hepatitis B, IPV Hepatitis B and Hib Hib, DTaP- can only be used as booster dose of Hib Hepatitis A and B- only approved for adults 11