Hib vaccine

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Hib vaccine
Hib for infanrix hexa.jpg
Hib component of Infanrix hexa
Vaccine description
Target Haemophilus influenzae type b
Vaccine type Conjugate
Clinical data
Trade names ActHIB, Hiberix, OmniHIB, others
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Hib vaccine
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The Haemophilus influenzae type B vaccine, also known as Hib vaccine, is a vaccine used to prevent Haemophilus influenzae type b (Hib) infection. [2] [3] In countries that include it as a routine vaccine, rates of severe Hib infections have decreased more than 90%. [2] It has therefore resulted in a decrease in the rate of meningitis, pneumonia, and epiglottitis. [2]

Contents

It is recommended by both the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC). [2] [4] Two or three doses should be given before six months of age. [2] In the United States a fourth dose is recommended between 12 and 15 months of age. [5] The first dose is recommended around six weeks of age with at least four weeks between doses. [2] If only two doses are used, another dose later in life is recommended. [2] It is given by injection into a muscle. [2]

Severe side effects are extremely rare. [2] About 20 to 25% of people develop pain at the site of injection while about 2% develop a fever. [2] There is no clear association with severe allergic reactions. [2] The Hib vaccine is available by itself, in combination with the diphtheria/tetanus/pertussis vaccine, and in combination with the hepatitis B vaccine, among others. [2] All Hib vaccines that are currently used are conjugate vaccine. [2]

An initial Hib vaccine consisting of plain (unconjugated) type b polysaccharide, was introduced in the United States in 1985. [6] but was replaced by a more effective conjugated formulations beginning in 1987. [7] As of 2013, 184 countries include it in their routine vaccinations. [2] It is on the World Health Organization's List of Essential Medicines. [8] [9]

Medical uses

Hib conjugate vaccines have been shown to be effective against all manifestations of Hib disease, with a clinical efficacy among fully vaccinated children estimated to be between 95–100%. The vaccine has also been shown to be immunogenic in patients at high risk of invasive disease. Hib vaccine is not effective against non-type B Haemophilus influenzae. However, non-type B disease is rare in comparison to pre-vaccine rates of Haemophilus influenzae type B disease. [10]

Impact

Prior to introduction of the conjugate vaccine, Hib was a leading cause of childhood meningitis, pneumonia, and epiglottitis in the United States, causing an estimated 20,000 cases a year in the early 1980s. Nearly all disease was in children under five years old. [11] After routine use of Hib conjugate vaccines in the United States, the rate of invasive Hib disease decreased from 40–100 per 100,000 children down to fewer than 1 per 100,000. [12] Similar reductions in Hib disease occurred after introduction of the vaccine in Western Europe [13] and developing countries. [14] However, in recent years. Haemophilus influenzae strains with other encapsulated serotypes such as a or f, or non-encapsulated strains, have been recognized to cause invasive disease, particularly in high risk populations. [14]

Recommendations

The CDC and the WHO recommend that all infants be vaccinated using a polysaccharide-protein conjugate Hib vaccine, starting after the age of six weeks. The vaccination is also indicated in people without a spleen. [15]

Side effects

Clinical trials and ongoing surveillance have shown Hib vaccine to be safe. In general, adverse reactions to the vaccine are mild. The most common reactions are mild fever, loss of appetite, transient redness, swelling, or pain at the site of injection, occurring in 5–30% of vaccine recipients. More severe reactions are extremely rare.[ citation needed ]

Mechanisms of action

Polysaccharide vaccine

Haemophilus influenzae type b is a bacterium with a polysaccharide capsule; the main component of this capsule is polyribosyl ribitol phosphate (PRP). Anti-PRP antibodies have a protective effect against Hib infections.  However, the antibody response to PRP was quite variable in young children, and diminished rapidly after administration. This problem was due to recognition of the PRP antigen by B cells, but not T cells. In other words, even though B cell recognition was taking place, T cell recruitment (via MHC class II) was not, which compromised the immune response. This interaction with only B cells is termed T-independent (TI). This process also inhibits the formation of memory B cells, thus compromising long term immune system memory. [16] [17]

Conjugate vaccine

PRP covalently linked to a protein carrier was found to elicit a greater immune response than the polysaccharide form of the vaccine. This is due to the protein carrier being highly immunogenic in nature. The conjugate formulations show responses which are consistent with T-cell recruitment (namely a much stronger immune response). A memory effect (priming of the immune system against future attack by Hib) is also observed after administration; indicative that memory B cell formation is also improved over that of the unconjugated polysaccharide form. Since optimal contact between B cells and T cells is required (via MHC II) to maximize antibody production, it is reasoned that the conjugate vaccine allows B cells to properly recruit T cells, this is in contrast to the polysaccharide form in which it is speculated that B cells do not interact optimally with T cells leading to the TI interaction. [16] [17]

Developing world

Introduction of Hib vaccine in developing countries lagged behind that in developed countries for several reasons. The expense of the vaccine was large in comparison to the standard EPI vaccines. Poor disease surveillance systems and inadequate hospital laboratories failed to detect the disease, leading many experts to believe that Hib did not exist in their countries. And health systems in many countries were struggling with the current vaccines they were trying to deliver.

GAVI and the Hib Initiative

In order to remedy these issues, the GAVI Alliance took active interest in the vaccine. GAVI offers substantial subsidization of Hib vaccine for countries interested in using the vaccine, as well as financial support for vaccine systems and safe injections. In addition, GAVI created the Hib Initiative to catalyze uptake of the vaccine. The Hib Initiative uses a combination of collecting and disseminating existing data, research, and advocacy to assist countries in the making a decision about using the Hib vaccine. Currently, 61 out of 72 low-income countries are planning on introducing the vaccine by the end of 2009. [18]

History

Polysaccharide vaccine

The first Hib vaccine licensed was a unconjugated polysaccharide vaccine, called PRP. This vaccine was first marketed in the United States in 1985. [19] Similar to other unconjugated polysaccharide vaccines, serum antibody responses to PPP vaccine were highly age-dependent. Children under 18 months of age did not produce a positive response for this vaccine. As a result, the age group with the highest incidence of Hib disease was unprotected, limiting the usefulness of the vaccine. Also, post-licensure studies by Michael Osterholm [20] and his colleagues,  and Dan Granoff et al. [21] suggested that the PRP vaccine was largely ineffective in preventing invasive Hib disease in children 18 to 59 months, the age group recommended for vaccination . The vaccine was withdrawn from the market in 1988. [22]

Conjugate vaccine

The shortcomings of the polysaccharide vaccine led to the production of the Hib polysaccharide-protein conjugate vaccine. [19] In 1987, the first Hib conjugate vaccine, which used diphtheria toxoid as the carrier protein (PRP-D), was licensed in the U.S. and initially recommended for children ages 18 to 59 months of age. [23] This vaccine was based on work done by American scientists John Robbins and Rachel Schneerson. [24] Attaching Hib polysaccharide to a protein carrier greatly increased the ability of the immune system of young children to recognize the polysaccharide and develop immunity. In contrast to unconjugated PRP vaccine, PRP-D vaccines was highly effective in controlling Hib disease in the age group being immunized (18 to 59 months). Unexpectedly. the vaccine also was associated with a dramatic decline in Hib disease in the age group less than 18 months, which was not being vaccinated (evidence of indirect community protection or “herd immunity”. [25]   Trudy Murphy and her colleagues reported that healthy children in a day care center who had been immunized with PRP-D had a lower rate of Hib colonization in their noses and throats than healthy unvaccinated children, which was not observed in children vaccinated with unconjugated PRP vaccine. [26]   These results provided an explanation for the ability of PRP-D conjugate vaccine to lower transmission of Hib from conjugate-vaccinated to unvaccinated children, and provide indirect community protection from conjugate vaccination .

There are currently three types of conjugate vaccine, utilizing different carrier proteins for the conjugation process: inactivated tetanospasmin (also called tetanus toxoid); mutant diphtheria protein; and meningococcal group B outer membrane protein. [27]

Combination vaccines

Multiple combinations of Hib and other vaccines have been licensed in the United States, reducing the number of injections necessary to vaccinate a child. Hib vaccine combined with diphtheria-tetanus-pertussis–polio vaccines and hepatitis B vaccines are available in the United States. The World Health Organization (WHO) has certified several Hib vaccine combinations, including a pentavalent diphtheria-pertussis-tetanus-hepatitis B-Hib, for use in developing countries. There is not yet sufficient evidence on how effective this combined pentavalent vaccine is in relation to the individual vaccines. [28]

Related Research Articles

ATC code J07Vaccines is a therapeutic subgroup of the Anatomical Therapeutic Chemical Classification System, a system of alphanumeric codes developed by the World Health Organization (WHO) for the classification of drugs and other medical products. Subgroup J07 is part of the anatomical group J Antiinfectives for systemic use.

<span class="mw-page-title-main">DPT vaccine</span> Combination vaccine

The DPT vaccine or DTP vaccine is a class of combination vaccines against three infectious diseases in humans: diphtheria, pertussis, and tetanus. The vaccine components include diphtheria and tetanus toxoids and either killed whole cells of the bacterium that causes pertussis or pertussis antigens. The term toxoid refers to vaccines which use an inactivated toxin produced by the pathogen which they are targeted against to generate an immune response. In this way, the toxoid vaccine generates an immune response which is targeted against the toxin which is produced by the pathogen and causes disease, rather than a vaccine which is targeted against the pathogen itself. The whole cells or antigens will be depicted as either "DTwP" or "DTaP", where the lower-case "w" indicates whole-cell inactivated pertussis and the lower-case "a" stands for "acellular". In comparison to alternative vaccine types, such as live attenuated vaccines, the DTP vaccine does not contain the pathogen itself, but rather uses inactivated toxoid to generate an immune response; therefore, there is not a risk of use in populations that are immune compromised since there is not any known risk of causing the disease itself. As a result, the DTP vaccine is considered a safe vaccine to use in anyone and it generates a much more targeted immune response specific for the pathogen of interest.

<i>Haemophilus influenzae</i> Species of bacterium

Haemophilus influenzae is a Gram-negative, non-motile, coccobacillary, facultatively anaerobic, capnophilic pathogenic bacterium of the family Pasteurellaceae. The bacteria are mesophilic and grow best at temperatures between 35 and 37 °C.

<span class="mw-page-title-main">Conjugate vaccine</span> Type of vaccine

A conjugate vaccine is a type of subunit vaccine which combines a weak antigen with a strong antigen as a carrier so that the immune system has a stronger response to the weak antigen.

<span class="mw-page-title-main">Pneumococcal polysaccharide vaccine</span> Pneumonia vaccine

Pneumococcal polysaccharide vaccine, sold under the brand name Pneumovax 23, is a pneumococcal vaccine that is used for the prevention of pneumococcal disease caused by the 23 serotypes of Streptococcus pneumoniae contained in the vaccine as capsular polysaccharides. It is given by intramuscular or subcutaneous injection.

<span class="mw-page-title-main">Childhood immunizations in the United States</span>

The schedule for childhood immunizations in the United States is published by the Centers for Disease Control and Prevention (CDC). The vaccination schedule is broken down by age: birth to six years of age, seven to eighteen, and adults nineteen and older. Childhood immunizations are key in preventing diseases with epidemic potential.

<span class="mw-page-title-main">Pneumococcal vaccine</span> Vaccine to prevent infection by the bacteria Stretococcus pneumoniae

Pneumococcal vaccines are vaccines against the bacterium Streptococcus pneumoniae. Their use can prevent some cases of pneumonia, meningitis, and sepsis. There are two types of pneumococcal vaccines: conjugate vaccines and polysaccharide vaccines. They are given by injection either into a muscle or just under the skin.

<span class="mw-page-title-main">Hepatitis B vaccine</span> Vaccine against hepatitis B

Hepatitis B vaccine is a vaccine that prevents hepatitis B. The first dose is recommended within 24 hours of birth with either two or three more doses given after that. This includes those with poor immune function such as from HIV/AIDS and those born premature. It is also recommended that health-care workers be vaccinated. In healthy people, routine immunization results in more than 95% of people being protected.

John Bennett Robbins was a senior investigator at the National Institutes of Health (NIH), best known for his contribution to the development of the vaccine against bacterial meningitis Hib)) with his colleague Rachel Schneerson. He conducted research on the Bethesda, Maryland campus of the NIH from 1970 until his retirement at the age of 80 in 2012. During his tenure, he worked in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the Food and Drug Administration’s biologics laboratories on location.

<span class="mw-page-title-main">Pertussis vaccine</span> Vaccine protecting against whooping cough

Pertussis vaccine is a vaccine that protects against whooping cough (pertussis). There are two main types: whole-cell vaccines and acellular vaccines. The whole-cell vaccine is about 78% effective while the acellular vaccine is 71–85% effective. The effectiveness of the vaccines appears to decrease by between 2 and 10% per year after vaccination with a more rapid decrease with the acellular vaccines. The vaccine is only available in combination with tetanus and diphtheria vaccines. Pertussis vaccine is estimated to have saved over 500,000 lives in 2002.

Meningococcal vaccine refers to any vaccine used to prevent infection by Neisseria meningitidis. Different versions are effective against some or all of the following types of meningococcus: A, B, C, W-135, and Y. The vaccines are between 85 and 100% effective for at least two years. They result in a decrease in meningitis and sepsis among populations where they are widely used. They are given either by injection into a muscle or just under the skin.

Haemophilus meningitis is a form of bacterial meningitis caused by the Haemophilus influenzae bacteria. It is usually associated with Haemophilus influenzae type b. Meningitis involves the inflammation of the protective membranes that cover the brain and spinal cord. Haemophilus meningitis is characterized by symptoms including fever, nausea, sensitivity to light, headaches, stiff neck, anorexia, and seizures. Haemophilus meningitis can be deadly, but antibiotics are effective in treating the infection, especially when cases are caught early enough that the inflammation has not done a great deal of damage. Before the introduction of the Hib vaccine in 1985, Haemophilus meningitis was the leading cause of bacterial meningitis in children under the age of five. However, since the creation of the Hib vaccine, only two in every 100,000 children contract this type of meningitis. Five to ten percent of cases can be fatal, although the average mortality rate in developing nations is seventeen percent, mostly due to lack of access to vaccination as well as lack of access to medical care needed to combat the meningitis.

A Vaccine Information Statement (VIS) is a document designed by the Centers for Disease Control and Prevention (CDC) to provide information to a patient receiving a vaccine in the United States. The National Childhood Vaccine Injury Act requires that medical professionals provide a VIS to patients before receiving certain vaccinations. The VIS includes information about the vaccine's benefits and risks, a description of the vaccine, indications and contraindications, instructions for patients experiencing an adverse reaction, and additional resources.

<span class="mw-page-title-main">Tetanus vaccine</span> Vaccines used to prevent tetanus

Tetanus vaccine, also known as tetanus toxoid (TT), is a toxoid vaccine used to prevent tetanus. During childhood, five doses are recommended, with a sixth given during adolescence.

DTaP-IPV/Hib vaccine is a 5-in-1 combination vaccine that protects against diphtheria, tetanus, whooping cough, polio, and Haemophilus influenzae type B.

DTaP-IPV-HepB vaccine is a combination vaccine whose generic name is diphtheria and tetanus toxoids and acellular pertussis adsorbed, hepatitis B (recombinant) and inactivated polio vaccine or DTaP-IPV-Hep B. It protects against the infectious diseases diphtheria, tetanus, pertussis, poliomyelitis, and hepatitis B.

DPT-Hib vaccine is a combination vaccine whose generic name is diphtheria and tetanus toxoids and whole-cell pertussis vaccine adsorbed with Hib conjugate vaccine, sometimes abbreviated to DPT-Hib. It protects against the infectious diseases diphtheria, tetanus, pertussis, and Haemophilus influenzae type B.

DTaP-Hib vaccine is a combination vaccine whose generic name is diphtheria and tetanus toxoids and acellular pertussis adsorbed with Haemophilus B conjugate vaccine, sometimes abbreviated to DTaP-Hib. It protects against the infectious diseases diphtheria, tetanus, pertussis, and Haemophilus influenzae type B.

<span class="mw-page-title-main">Hexavalent vaccine</span> Single vaccine protecting against six individual diseases

A hexavalent vaccine, or 6-in-1 vaccine, is a combination vaccine with six individual vaccines conjugated into one, intended to protect people from multiple diseases. The term usually refers to the children's vaccine that protects against diphtheria, tetanus, pertussis, poliomyelitis, haemophilus B, and hepatitis B, which is used in more than 90 countries around the world including in Europe, Canada, Australia, Jordan, and New Zealand.

Trudy Virginia Noller Murphy is an American pediatric infectious diseases physician, public health epidemiologist and vaccinologist. During the 1980s and 1990s, she conducted research at Southwestern Medical School in Dallas, Texas on three bacterial pathogens: Haemophilus influenzae type b (Hib), Streptococcus pneumoniae (pneumococcus), and methicillin-resistant Staphylococcus aureus (MRSA). Murphy's studies advanced understanding of how these organisms spread within communities, particularly among children attending day care centers. Her seminal work on Hib vaccines elucidated the effects of introduction of new Hib vaccines on both bacterial carriage and control of invasive Hib disease. Murphy subsequently joined the National Immunization Program at the Centers for Disease Control and Prevention (CDC). where she led multi-disciplinary teams in the Divisions of Epidemiology and Surveillance and The Viral Hepatitis Division. Among her most influential work at CDC was on Rotashield™, which was a newly licensed vaccine designed to prevent severe diarrheal disease caused by rotavirus. Murphy and her colleagues uncovered that the vaccine increased the risk of acute bowel obstruction (intussusception). This finding prompted suspension of the national recommendation to vaccinate children with Rotashield, and led the manufacturer to withdraw the vaccine from the market. For this work Murphy received the United States Department of Health and Human Services Secretary's Award for Distinguished Service in 2000, and the publication describing this work was recognized in 2002 by the Charles C. Shepard Science Award from the Centers for Disease Control and Prevention.

References

  1. ↑ Professional Drug Facts
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 World Health Organization (September 2013). "Haemophilus influenzae type b (Hib) Vaccination Position Paper – July 2013". Weekly Epidemiological Record. 88 (39): 413–426. hdl:10665/242126. PMID   24143842.
  3. ↑ "WHO position on Haemophilus influenzae type b (Hib) vaccination‐July 2013" (PDF). who.int. 27 October 2013. Archived from the original (PDF) on 19 January 2022. Retrieved 30 March 2016.
  4. ↑ "Haemophilus b conjugate vaccines for prevention of Haemophilus influenzae type b disease among infants and children two months of age and older. Recommendations of the immunization practices advisory committee (ACIP)". MMWR. Recommendations and Reports. cdc.gov. 40 (RR-1): 1–7. January 1991. PMID   1899280.
  5. ↑ "Hib (Haemophilus Influenzae Type B)". Archived from the original on 8 April 2016. Retrieved 30 March 2016.
  6. ↑ Cochi SL, Fleming DW, Hull HF, Preblud SR, Orenstein WA (December 1986). "Haemophilus influenzae b polysaccharide vaccine. Physician acceptance and use of a new vaccine". American Journal of Diseases of Children. 140 (12): 1226–1230. doi:10.1001/archpedi.1986.02140260028019. PMID   3490784.
  7. ↑ Weinberg GA, Granoff DM (October 1988). "Polysaccharide-protein conjugate vaccines for the prevention of Haemophilus influenzae type b disease". The Journal of Pediatrics. 113 (4): 621–631. doi:10.1016/S0022-3476(88)80369-X. PMID   3050001.
  8. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019 (PDF). Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  9. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl: 10665/345533 . WHO/MHP/HPS/EML/2021.02.
  10. ↑ Cox AD, Kuo Lee R, Ulanova M, Bruce MG, Tsang RS (January 2021). "Proceedings of a workshop to discuss the epidemiology of invasive Haemophilus influenzae disease with emphasis on serotype a and b in the Americas, 2019". Vaccine. 39 (4): 627–632. doi:10.1016/j.vaccine.2020.12.015. PMID   33358264. S2CID   229695991.
  11. ↑ Broome CV (August 1987). "Epidemiology of Haemophilus influenzae type b infections in the United States". The Pediatric Infectious Disease Journal. 6 (8): 779–782. doi:10.1097/00006454-198708000-00036. PMID   3313240.
  12. ↑ "Haemophilus influenzae Disease (Including Hib)". U.S. Centers for Disease Control and Prevention (CDC). 25 September 2012. Archived from the original on 30 January 2014. Retrieved 31 January 2014.
  13. ↑ Whittaker R, Economopoulou A, Dias JG, Bancroft E, Ramliden M, Celentano LP (March 2017). "Epidemiology of Invasive Haemophilus influenzae Disease, Europe, 2007-2014". Emerging Infectious Diseases. 23 (3): 396–404. doi:10.3201/eid2303.161552. PMC   5382729 . PMID   28220749.
  14. 1 2 Slack MP, Cripps AW, Grimwood K, Mackenzie GA, Ulanova M (June 2021). "Invasive Haemophilus influenzae Infections after 3 Decades of Hib Protein Conjugate Vaccine Use". Clinical Microbiology Reviews. 34 (3): e0002821. doi:10.1128/CMR.00028-21. PMC   8262803 . PMID   34076491.
  15. ↑ "Asplenia and Adult Vaccination". U.S. Centers for Disease Control and Prevention (CDC). 14 February 2019. Retrieved 29 March 2019.
  16. 1 2 Kelly DF, Moxon ER, Pollard AJ (October 2004). "Haemophilus influenzae type b conjugate vaccines". Immunology. 113 (2): 163–174. doi:10.1111/j.1365-2567.2004.01971.x. PMC   1782565 . PMID   15379976.
  17. 1 2 Finn A (1 January 2004). "Bacterial polysaccharide-protein conjugate vaccines". British Medical Bulletin. 70 (1): 1–14. doi: 10.1093/bmb/ldh021 . PMID   15339854.
  18. ↑ "Hib Initiative". Archived from the original on 5 September 2008. Retrieved 3 October 2008. 61 of 72 GAVI countries have introduced or will introduce Hib vaccine into their routine immunization program [ sic ] by 2009
  19. 1 2 Centers for Disease Control and Prevention (2006). Atkinson W, Hamborsky J, McIntyre L, Wolfe S (eds.). Epidemiology and Prevention of Vaccine-Preventable Diseases (9th ed.). Washington, D.C.: Public Health Foundation.
  20. ↑ Osterholm MT, Rambeck JH, White KE, Jacobs JL, Pierson LM, Neaton JD, et al. (September 1988). "Lack of efficacy of Haemophilus b polysaccharide vaccine in Minnesota". JAMA. 260 (10): 1423–1428. doi:10.1001/jama.1988.03410100113035. PMID   3261350.
  21. ↑ Granoff DM, Shackelford PG, Suarez BK, Nahm MH, Cates KL, Murphy TV, et al. (December 1986). "Hemophilus influenzae type B disease in children vaccinated with type B polysaccharide vaccine". The New England Journal of Medicine. 315 (25): 1584–1590. doi:10.1056/NEJM198612183152505. PMID   3491315.
  22. ↑ Zarei AE, Almehdar HA, Redwan EM (20 January 2016). "Hib Vaccines: Past, Present, and Future Perspectives". Journal of Immunology Research. 2016: 7203587. doi: 10.1155/2016/7203587 . PMC   4745871 . PMID   26904695.
  23. ↑ "American Academy of Pediatrics Committee on Infectious Diseases: Haemophilus influenzae type b conjugate vaccine". Pediatrics. 81 (6): 908–911. June 1988. PMID   3259309.
  24. ↑ "Haemophilus influenzae type b (Hib)". historyofvaccines.org. Retrieved 8 May 2023.
  25. ↑ Murphy TV, White KE, Pastor P, Gabriel L, Medley F, Granoff DM, Osterholm MT (January 1993). "Declining incidence of Haemophilus influenzae type b disease since introduction of vaccination". JAMA. 269 (2): 246–248. doi:10.1001/jama.1993.03500020080036. PMID   8417244.
  26. ↑ Murphy TV, Pastor P, Medley F, Osterholm MT, Granoff DM (April 1993). "Decreased Haemophilus colonization in children vaccinated with Haemophilus influenzae type b conjugate vaccine". The Journal of Pediatrics. 122 (4): 517–523. doi:10.1016/s0022-3476(05)83529-2. PMID   8463894.
  27. ↑ Kelly DF, Moxon ER, Pollard AJ (October 2004). "Haemophilus influenzae type b conjugate vaccines". Immunology. 113 (2): 163–174. doi:10.1111/j.1365-2567.2004.01971.x. PMC   1782565 . PMID   15379976.
  28. ↑ Bar-On ES, Goldberg E, Hellmann S, Leibovici L (April 2012). "Combined DTP-HBV-HIB vaccine versus separately administered DTP-HBV and HIB vaccines for primary prevention of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae B (HIB)". The Cochrane Database of Systematic Reviews (4): CD005530. doi:10.1002/14651858.CD005530.pub3. PMID   22513932.

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