Pertussis Vaccine Adsorbed; Acellu-lar Pertussis -Vaccine Adsorbed; [components of DTP/DTaP]

Organizations involved (historically):

Div. of Biologics Standards, NIH – R&D; Tech.

Cross ref: See the entries for Acellular Pertussis Vaccine Products (#506), and Diphtheria and Pertussis Toxoids and Pertussis (DTP/DTaP) Vaccine Products (#429).

Description: Pertussis Vaccine, Pertussis Vaccine Adsorbed, and Acellular Pertussis Vaccine Adsorbed are the three types of pertussis (whooping cough) vaccines having received FDA approval. Each contains formaldehyde (or other reactive agent) inactivated antigens obtained from culture of Bordetella pertussis bacteria. Pertussis Vaccine and Pertussis Vaccine Adsorbed contain purified, inactivated, whole bacterial cells, optionally adsorbed onto aluminum adjuvant. Acellular Pertussis Vaccine Adsorbed contains purified, inactivated, bacterial antigens (often different for each vaccine), with no significant levels of whole bacterial cells.

Nomenclature: Pertussis Vaccine [FDA]; Pertussis Vaccine Adsorbed [FDA]; Acellular Pertussis Vaccine Adsorbed [FDA]; Pertussis Topagen [TR former]; Serobacterin pertussis [TR old]; Solgen [TR former]

Biological.: All pertussis vaccines include inactivated pertussis toxin (PT; pertussis toxoid). This Bordetella pertussis bacterium PT exotoxin protein is a member of the A/B family of bacterial toxins with ADP-ribosyltransferase activity. PT has been proposed as a major virulence factor for and protective antigen against B. pertussis infection and disease (whooping cough). The A protein chain of this toxin exhibits ADP-ribosyltransferase activity, and the B protein chain mediates binding of the toxin to host cell receptors and the translocation of the A chain to its site of activity (toxicity) within the cell. PT also facilitates the adherence of B. pertussis to ciliated epithelial cells and also plays a role in the invasion of macrophages by B. pertussis.

The main pathophysiological effects of PT are due to its ADP-ribosyltransferase activity. PT catalyses the transfer of ADP-ribose from NAD to the Gi guanine nucleotide-binding protein, disrupting the cellular adenylate cyclase regulatory system. PT also prevents the migration of macrophages and lymphocytes to sites of inflammation and interferes with the neutrophil-mediated phagocytosis and killing of bacteria. When exposed to PT, Chinese hamster ovary (CHO) cells develop a characteristic clustered morphology. This CHO cell clustering assay is widely used to test the integrity and toxicity of PT holotoxins.

Natural infection with B. pertussis generates both humoral and cell-mediated responses to PT. Infants have transplacentally-transferred anti-PT antibodies. PT antibodies are found in human colostrum and are also transmitted transplacentally. A cell-mediated immune response to PT subunits has been demonstrated after immunization with both acellular and whole cell vaccines. Inactivated PT in whole-cell or acellular vaccines is protective in animal models and in humans.

B. pertussis filamentous hemagglutinin (FHA) is a large (220 kDa) non-toxic but immunogenic B. pertussis polypeptide antigen that mediates attachment of B. pertussis to ciliated cells of the upper respiratory tract during bacterial colonization. Natural infection induces anti-FHA antibodies and cell-mediated immune responses. FHA antibodies are found in human colostrum and are also transmitted transplacentally. Vaccination with a whole-cell or acellular pertussis vaccine containing FHA generates FHA-specific antibodies. Acellular vaccines containing FHA also induce a cellular immune response, e.g., targeted cytotoxic T lymphocytes, to FHA.

The B. pertussis 69 kDa Outer Membrane Protein (pertac-tin; P69) antigen binds directly to eukaryotic cells. Natural infection with B. pertussis induces an anti-P69 humoral antibody response, and P69 also induces a cell-mediated immune response. Vaccination with whole-cell or acellular vaccines containing p69 induces P69 antibodies, and acellular vaccines containing p69 also induce P69 cellular immune responses.

Serotypes of B. pertussis are defined by their agglutinating fimbriae. The WHO recommends that whole-cell vaccines include types 1, 2 and 3 agglutinogens (Aggs) since they are not cross-protective. Agg 1 is non-fimbrial and is found on all B. pertussis strains. Serotype 2 and 3 Aggs are fimbrial. Natural infection or immunization with whole-cell or acellular vaccines (containing fimbrial or other Agg) induces anti-Agg antibodies. A specific cell-mediated immune response can be generated in mice by Agg 2 and Agg 3 after aerosol infection. Aggs 2 and 3 are protective in mice against respiratory challenge. Human colostrum containing anti-agglutinogens also provides protection in this assay.

History: Companies previously licensed for manufacture of Pertussis Vaccine (from CBER/FDA database): Bayer Corp. (Aug. 1914-Oct. 1970); Dow Chemical Co. (Oct. 1932-June 1977); Eli Lilly & Co. (March 1915-March 1978); Lederle Labs. (Jan. 1914-May 1980); Merrell-National Labs., Richard-son-Merrell Inc. (Oct. 1926-Jan. 1978; acquired by Connaught Labs.); Michigan Biologic Products Inst. (Nov. 1935-Feb. 1977); Parke-Davis div. of Warner-Lambert Co. (April 1952-Oct. 1981); Texas Dept. of Health Resources (Dec. 1954-Feb. 1979); and Wyeth Labs. (July 1952-May 1987). Other 1914 approvals for Pertussis Vaccine reported by other sources (but no longer reported by FDA, which has lost much older vaccine approval records) include Dr. C.L. McDonald; E.R. Squibb & Sons, Inc.; Sherman Labs.; and Upjohn Co.

Companies previously licensed to manufacture Pertussis Vaccine Adsorbed: Bayer Corp. (Sept. 1948-Oct. 1970); Michigan Biologic Products Inst. (Oct. 1967-Nov. 1998; now BioPort Corp.); and Parke-Davis div., Warner-Lambert Co. (Feb. 1952-Oct. 1981).

Pertussis vaccines had been available since 1915, but results from their use were not entirely satisfactory due to lack of assays/standards for vaccine potency. In 1944, Dr. M. Pittman, Biologics Control Laboratory (later part of NIAID, NIH; later became CBER, FDA), developed a potency assay in mice for pertussis vaccines, allowing standardization of potency. See A Life with Biological Products, by M. Pittman. This development was based on recognition that the primary antigen was a bacterial exotoxin. By 1949, manufacturers were selling whooping cough vaccine approved based on potency as well as on safety and sterility.

Manufacture: manufacture of whole cell pertussis vaccines essentially involves culture of the bacteria, inactivation, and purification. See the individual vaccine entries for further manufacturing information.

Quality control criteria for Pertussis Vaccines are described in the Code of Federal Regulations, Title 21, section 620.1 through 620.6 (21 CFR 620.1-620.6). The U.S. Pharmacopoeia (USP) standard for Pertussis Vaccines describes mouse (murine) challenge tests that measure protection by a standard dose of vaccine after intracerebral challenge (injection with pathogenic B. pertussis).     

The mouse weight-gain test was formerly used for testing the toxicity of whole-cell pertussis vaccines. Acellular pertussis and DTaP vaccines are tested specifically for residual pertussis toxin (PT) activity.

Status: Since 1997, acellular, rather then whole cell, pertussis vaccines have been preferred for all doses in the pediatric immunization schedule recommended by CDC’s Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP), i.e., acellular vaccines have largely replaced whole cell vaccines. Recommendations favoring use of acellular over whole cell pertussis vaccines for pediatric vaccination were promulgated as early as 1992.

Infants/children in the U.S. are now generally required to receive four doses of a combined diphtheria, tetanus and pertussis (DTP or DTaP) vaccine during the first two years of life, and a fifth dose administered prior to entering grade school, i.e., pertussis is a universal or required pediatric vaccine. As such, it is included in the federal vaccine liability insurance program (see #400).

The introduction of whole-cell vaccines composed of chemically- and heat-inactivated B. pertussis organisms in the 1940’s was responsible for a dramatic reduction in the incidence of whooping cough caused by B. pertussis. The efficacy rates for whole-cell vaccines have been estimated at up to 95%, depending on case definition.

Adverse effects from pertussis vaccines and the relative benefits and safety of DTP vs. DTaP vaccines have been extensively studied, and have been and remain highly controversial. Adverse events associated with these vaccines are generally attributed to the pertussis vaccine component, particularly whole cell pertussis vaccine. Adverse effects occur at very low rates, but are noticeable due to the universal use of these vaccines.

Whole cell pertussis vaccines (usually administered as DTP vaccine) have a noticeable and, what is considered by many, an excessively high rate of mild and severe side effects. Mild side effects include pain and tenderness where the shot was given, fever, fretfulness, and drow-siness. These mild side effects occur in as many as one-half to one-third of children who receive the vaccine. Severe side effects, such as persistent, inconsolable crying occur in 1/100 doses, fever greater than 105˚F in 1/330 doses, and seizures with fever in 1/1,750 doses. More severe side effects, including death, have been associated with whole cell B. pertussis vaccines, including encephalopathy, convulsions, shock, collapse, focal neurological disease, etc. Peripheral neuropathy may be due to vaccination too close to a nerve. The Institute of Medicine, National Academy of Sciences (NAS), has found that whole cell pertussis component DTP vaccines are associated with acute encephalopathy, shock and a distinct shock-like state, anaphylaxis, and unstoppable crying. Despite increased risks using whole cell pertussis DTP vaccines, these are still used, including by public health vaccination programs, because they effective, still provide what many consider to be a good risk-benefit ratio, and are much less expensive than DTaP vaccines.

Newer acellular pertussis vaccines have a rate of both mild and severe side effects that is at least 10-fold lower than that for whole cell vaccines.

The incidence of B. pertussis infection and mortality from pertussis disease, e.g., whooping cough, general declines with increasing age, while the risk for adverse events from vaccination increases with age. Thus, vaccination of unvaccinated persons over age seven is generally not recommended. Combined tetanus and diphtheria toxoid (Td) vaccines (no pertussis component), are preferred for older children and adults not having previously received a primary course of pertussis vaccinations.

The U.S. experienced a severe shortage of tetanus toxoid and tetanus toxoid-containing vaccines, including DTP and DTaP vaccines containing tetanus toxoid as a component starting in 2000 when two manufacturers of tetanus toxoid and DTaP (Wyeth and North American Vaccine, Inc./Baxter Hyland Immuno Vaccines,) halted manufacture of these products, leaving only Aventis Pasteur (Sanofi Aventis) and GlaxoSmithKline to supply the U.S. market. The shortage lasted into early 2002, when Aventis Pasteur (the largest manufacturer) expanded its supplies and was able to fulfill the complete U.S. demand for tetanus toxoid-containing vaccines.

In Oct. 2005, the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC), voted unanimously to recommend that all non-elderly adults receive a pertussis booster, with this expected to be in the form of a diphtheria, tetanus and pertussis booster vaccination (dTap vaccine).

Medical: The current U.S. childhood immunization schedule recommends five doses of a DTP/DTaP vaccine before school entry to adequately protect children. The suggested ages of administration are 2, 4 and 6 months; 15 to 20 months (first booster dose); and at 4-6 years (second booster dose or “preschool booster”).

Persons over age seven are generally not recommended to receive full-dose pertussis vaccine due to increased risk for adverse effects and the likelihood that they have already had exposure to pertussis. This is the primary reason tetanus and diphtheria toxoid (Td) vaccines, now DTP or DTaP, are used as boosters in adults.

Disease: Besides serious health risks, pertussis also has a financial impact on the family. The average medical costs for a family with an infant with pertussis has been reported to be more than $2,800, and the parents lost an average of six days of work to care for an ill child. This loss of productivity cost families an average of $767. Another study, published in 2004, found that the majority of adults missed an average of 9.8 days of work due to their disease, while adolescents missed an average of 5.5 days of school.

In Dec. 2005, Centers for Disease Control and Prevention (CDC) reported that annual cases of whooping cough in the U.S. increased from a historic low of 1,010 in 1976 to 11,647 in 2003, and that a third of all new cases involve adolescents. In general, five doses of pertussis vaccine are administered by a child’s sixth birthday, but pertussis vaccine immune responses weaken and no longer afford adequate protection once a child turns 11 or 12 years of age. The CDC now urges this demographic to receive a pertussis booster vaccine (dTap).