Haemophilus influenzae type b conjugate vaccines; Hib; Meningitis vaccines

Organizations involved: [selected organizations involved in early technology development]

Rockefeller University – R&D; Tech.

Bureau of Biologics, NIH – R&D; Tech.

National Institutes of Health (NIH) – Parent

Cross ref: See the entries below for specific Haemophilus influenzae type b (Hib) vaccines, and the various combination vaccines incorporating a Hib component.

Description: Haemophilus influenzae type b conjugate vaccines or Hib vaccines are bacterial subunit polysaccharide vaccines composed of fragments of the bacterial outer capsular polysaccharide of Haemophilus influenzae type b (Hib) bacterium. Currently marketed products involve Hib polysaccharide chemically conjugated to a carrier protein, which acts to increase immune responses to the bacterial polysaccharide. Each of the available conjugated vaccines uses polysaccharide from different Hib strains. Immunogenicity, administration regimens, and other aspects of each vaccine may vary. However, the extent of protection from disease is comparable between the different products.

There are currently five Hib polysaccharide-carrier conjugate vaccines marketed in the U.S, with OmniHIB being identical to ActHib (relabeled). These vaccines involve H. influen-zae type b capsular polysaccharide (PRP) conjugated to either diphtheria toxoid, tetanus toxoid, or Neisseria menin-gitidis outer membrane protein. Generally, these vaccines are stored at 2-8˚C (refrigerated) with a shelf live of 24 months.

Biological.: Haemophilus influenzae type b (Hib; H. influenzae) is a facultative anaerobe, Gram-positive, rod-shaped, bacterium, a member of the Pasteurellaceae family of bacteria. Hib was previously referred to as influenza bacillus. Hib was first discovered in 1892 and mistakenly attributed as the cause for an influenza epidemic. The bacterium is protected from phagocytosis in vivo by its polysaccharide capsule composed of a repeating polymer of polyribosylribitol phosphate (PRP). Children often harbor Hib in their throats and infection is spread by respiratory fluids (e.g., sneezing, sharing of food).

The Hib bacterium capsule (outer cell membrane) is composed of polysaccharide polymers of ribose, ribitol, and phosphate or polyribosyl-ribitol-phosphate (PRP) containing the repeating unit [-3-beta-D-ribosyl(1-1)--ribitol-(5-phosphate)]. Generally, after obtaining PRP from fermentation of H. influenzae type b, PRP is subjected to acid hydrolysis and the resulting mixture of different sized fragments is fractionated by molecular sieve column chromatography to isolate desired size ranges of fragments for conjugation.

Hib PRP alone (unconjugated) does not induce proliferation of T-helper cells (desired for long-term response), and re--immunization with unconjugated Hib PRP fails to elicit either a booster response or an increase in memory cells. Unconjugated Hib vaccines are immunogenic in adults and in children older than 18 months of age, but fail to elicit immunity in infants, the age group at greatest risk for Haemophilus disease. Conjugation of the PRP polysaccharide with a protein carrier confers T-cell dependent characteristics to the vaccine, and substantially enhances the longer-term immune responses to the PRP antigen. Antibodies to the type b capsule confer protection against disease by initiating opsoni-zation and complement-dependent lysis of invading Hib bacteria.

Hib PRP and other bacterial polysaccharide antigens, by themselves, generally directly stimulate B-cells to produce IgG and IgM antibodies, but these antibody responses are not affected by subsequent boosters and do not provide adequate long-term immunity. Conjugation of the Hib polysaccharide to a suitable bacterial protein antigen carrier results in B-cell production of antibodies with involvement of T helper cells (T lymphocytes) with immunologic memory, resulting in primarily IgG antibodies, boosterable responses, and longer-lasting immunity (better antibody production in response to Hib infection). Circulating Hib antibody concentrations greater than or equal to 0.15 µg/ml correlate with protection from disease and levels over 1 µg/ml correlate with prolonged protection from disease, generally presumed to last at least five to seven years, although some studies suggest that protective immunity may persist even after antibodies are no longer detectable.

History: Early work by Dr. M. Pittman, Rockefeller University, and collaborators included discovery of encapsulated H. influenzae, identification of the type b encapsulated variety as the primary cause of disease in children, and identification of type B capsular polysaccharide. Drs. J. Robbins, R. Schneerson, M. Pittman, et al., Bureau of Biologics, National Institutes of Health (NIH), which later became CBER, FDA, in the 1970s-1980s developed the first polysaccharide-protein conjugate vaccines.

Several unconjugated Hib vaccines were approved by FDA in 1985. These included HIB-Vax from Pasteur Merieux Connaught, now Sanofi Pasteur; b-CAPSA-1 from Praxis (became part of Lederle Labs./Wyeth) and Mead Johnson; and HIB-Immune from Wyeth. Lederle Labs. held approval from Dec. 29, 1985 to Oct. 23, 1996 for manufacture of an uncon-jugated Haemophilus b Polysaccharide Vaccine. However, these unconjugated vaccines were not sufficiently effective in the most important high risk group, infants under age two.

The methods for conjugation of polysaccharides and proteins to enhance polysaccharide antigenicity were first developed in the 1920s. The first conjugate vaccine to receive approval was ProHIBiT from Pasteur Merieux Connaught (now Sanofi Aventis) in late 1987; and recommendations for its use in all children <18 months of age were issued in Jan. 1988.

Status: Regarding approved Indications: for Hib vaccines, in Aug. 1998 FDA stated, “The following is consistent with the currently approved labeling for Haemophilus influenzae type b (Hib) conjugate vaccines: a) For the immunization of children less than 15 months of age: Any licensed Hib conjugate vaccine may be given concurrently in separate sites with DTaP or Diphtheria and Tetanus Toxoids and Whole Cell Pertussis Vaccine (DTP) vaccine, according to the package insert. Alternatively, any of the licensed combination products containing DTP and Hib conjugate vaccine may be used. Please note that ACIP has a stated preference for products containing an acel-lular pertussis component. b) For the immunization of children 15 months of age or older: Any licensed Hib conjugate vaccine may be given concurrently in separate sites with DTaP or DTP vaccine. Alternatively, any of the licensed combination products containing DTP and Hib or TriHIBit may be used. Please note that ACIP has a stated preference for products containing an acellular pertussis component."

In Dec. 2007, Merck voluntarily recalled certain lots of two Haemophilus influenzae type b (Hib) conjugate vaccines (>1 million doses): PedvaxHIB (monovalent Hib vaccine) and Comvax (Hib/hepatitis B vaccine). Merck suspended production of its Hib conjugate vaccines and did not expect to resume distribution of these vaccines until the fourth quarter of 2008. Merck issued this voluntary recall as a precautionary measure because the company could not assure the sterility of equipment used during manufacture of these lots. However, the potency of the vaccine in the recalled lots was not affected, and no contamination of vaccine has been detected (so vaccine the market was OK). The two other U.S. Hib conjugate vaccines in the U.S., ActHIB (monovalent Hib vaccine) and TriHIBit (diphtheria and tetanus toxoids and acellular pertussis [DTaP]/Hib vaccine), were unaffected by the recall. However, Sanofi Pasteur was not expected to be able to immediately provide adequate Hib vaccine to vaccinate fully all children for whom the vaccine is recommended. In response, the CDC temporarily modified recommendations for vaccinations with Hib vaccines. Because of the short-term reduction in available doses of Hib-containing vaccines, CDC, in consultation with the Advisory Committee on Immunization Practices (ACIP), the American Academy of Family Physicians, and the American Academy of Pediatrics, recommended that providers temporarily defer administering the routine Hib vaccine booster dose administered at age 12--15 months except to children in specific groups at high risk. Providers were to register and track children for whom the booster dose is deferred to facilitate recalling them for vaccination when supply improves

Subsequent to the Merck recall of over 1.2 million doses starting in late 2007, Sanofi Pasteur strained to keep up with demand, but shortages developed and the number of reported cases of pneumococcal pneumonia in unvaccinated children rose.

The Aug. 2009 FDA approval of Hiberix from GSK as a booster was expected to help ease the shortage of Hib vaccines, and allow resumption of many of the normal vaccination schedules and programs.

Merck was expected to resolve its manufacturing problems and resume full manufacture in mid-to-late 2009.

Trials: Various studies have shown protein-conjugated Hib vaccines to be about 45% to 88% effective for reduction of invasive disease in children 18-24 months or older.

Disease: Haemophilus influenzae type b (Hib) is a major cause of bacterial meningitis in children under five years. Meningitis involves infection of the membranes covering the brain and spinal cord, potentially leading to paralysis, deafness, retardation, and death. There are six serotypes of Hib, designated a-f, defined by antigenic properties of their capsular polysaccharides. The current H. influenzae type b conjugate vaccines do not protect against other invasive typeable strains (types a and c); and do not protect against non-typeable (NTHi) strains, which are a common cause of postpartum and neonatal sepsis, pneumonia, and otitis media (infection involving ear ache). Hib primarily affects children under five years of age. Otitis media associated with Hib is the most common illness of early childhood, with approximately 70% of all children suffering at least one bout of otitis media before the age of seven.

Hib vaccination has been very successful in the U.S., and the disease has been nearly eradicated since introduction of Hib conjugate vaccines. Before effective vaccines became available in the U.S., Hib was the leading cause of bacterial meningitis and other serious diseases among children <5 years of age. Incidence rates in the U.S. for Hib meningitis fell significantly after vaccination programs were implemented in the late 1980s. In the mid-1980s, prior to widespread vaccination, the incidence rate in the U.S. among children less <5 years of age was 0.1%/year or about 20,000 cases/year (in 1987); risk of disease was about 1 in 200 by age five; and about one-half of disease was in those under age one and the other half in those aged 2-5. The mortality rate was 5%, and neurologic sequelae were observed in as many as 25%-35% of survivors. Only a few years later, in 1991, after implementation of vaccination programs using newer conjugate vaccines, the number of U.S. cases was down to 1,900.

On March 22, 2002, the Centers for Disease Control and Prevention (CDC) published “Progress Toward Elimination of Haemophilus influenzae Type b Invasive Disease Among Infants and Children–United States, 1998-2000” in the Morbidity and Mortality Weekly Report (MMWR). Compared with incidence from the pre-vaccine era, by 1996, due to the widespread use of Hib conjugate vaccines, the incidence of Hib invasive disease among children <5 years of age declined by >99%. Illness and death occurred mostly among young infants not completing the 2-dose (at 2 and 4 months of age) or 3-dose (2, 4, and 6 months of age) primary series of Hib vaccination, and unvaccinated or under-vaccinated older children.

Worldwide, where the majority of person have not received vaccination, there are an estimated 800,000 cases of Hib meningitis and about 150,000 deaths annually.

Market: Merck and Sanofi Pasteur both produce Hib vaccines, with each contributing approximately half of the 14 million doses administered in the U.S. annually.

Hib conjugate vaccines are not affordable or used in most lesser-developed countries. Most sales are in developed countries. The World Health Organization (WHO), United Nations, has estimated that 55 million doses of Hib vaccines were manufactured worldwide in 1996-1997.

In the July 30 2004 issue of Morbidity & Mortality Weekly Report (MMWR) [53(29);658-661], CDC estimated that 93.9% (±0.6) of U.S. infants (annual cohort ~4 million) had received ≥3 doses of a Hib vaccine.

Competition: The Serum Institute (India) has developed a Hib vaccine. The product was launched in India in April 2007. Serum Institute has a capacity to produce more than 100 million doses of the vaccine. The primary purchasers are expected to be the Global Alliance for Vaccines and Immunization (GAVI), the Pan American Health Organization (PAHO) and the United Nations Children’s Fund (UNICEF).

In Sept. 2007, Bharat Biotech International (India) launched BioHib, a Hib conjugate vaccine, in India. It also launched a tetravalent combination vaccine, Comvac4-HB, containing Diphtheria, Pertussis, Tetanus and Hepatitis B in one vaccine. These two new vaccines, BioHib and Comvac4-HB, enable the deployment of a combination pentavalent vaccine in a single injection.

R&D: In the July 23, 2004 issue of Science (305: 522-525), the Center for Genetic Engineering and Biotechnology (Cuba) reported GMP manufacture of a Haemophilus influenzae vaccine composed of a synthetic capsular polysaccharide antigen conjugated to tetanus toxoid (sPRP-TT). In early trials, the vaccine elicited antibody titers similar to other marketed vaccines.

BioVeris Corp. (Gaithersburg, MD) is developing Hib vaccines, including Neisseria meningitidis group Y and Haemophilus influenzae type b (Hib) components in new combination vaccine candidates using technology licensed from Baxter Healthcare Corp.