Pertussis

During the early 1900s, vaccines against major human epidemic diseases such as pertussis, diphtheria, tetanus, and tuberculosis were developed. Vaccines for many animal diseases were also available. In the early 1950s, the development of cell culture techniques byj. E. Enders at Harvard was followed by another series of major advances in vaccine development. Vaccines against poHo, mumps, measles, and mbeUa were Hcensed during the 1960s. 

Vaccines can be roughly categorized into killed vaccines and Hve vaccines. A killed vaccine can be (/) an inactivated, whole microorganism such as pertussis, (2) an inactivated toxin, called toxoid, such as diphtheria toxoid, or (J) one or more components of the microorganism commonly referred to as subunit vaccines. The examples are capsular polysaccharide of Streptococcus pneumoniae and the surface antigen protein for Hepatitis B vims vaccine. 

Diphtheria, Tetanus, and Pertussis. These vacciaes Hi combiaatioa (DTP) have beea routiaely used for active immunization of Hifants and young children sHice the 1940s. The recommended schedule calls for immunizations at 2, 4, and 6 months of age with boosters at 18 months and 4—5 years of age. SHice 1993 these vacciaes have beea available Hi combination with a vacciae that protects agaiast Haemophilus disease, thus providing protectioa agaiast four bacterial diseases Hi oae preparatioa. A booster immunization with diphtheria and tetanus only is recommended once every 10 years after the fifth dose. 

The final vacciae coataHis the two toxoids, as weU as pertussis (whole ceU or aceUular), a buffer, and an adjuvant, ie, a substance that Hicreases the response to an antigen when combHied with the antigen, eg, aluminum. As noted above, the final vacciae can also contain a component that protects against Haemophilus disease. 

The U.S. standard pertussis vacciae is used to standardize the potency of the whole ceU pertussis vacciae. The number of protective units Hi the vaccine is estimated for each lot from the results of simultaneous intracerebral mouse-protection tests of the vaccine being studied and the U.S. reference standard (14,17). The potency of the aceUular vaccines is estimated by then abUity to produce antibodies to the proteins Hi the vaccine Hi a mouse model. These vaccines also undergo a series of animal safety tests to ensure that the iaactivation and toxoiding steps were carried out correctiy (14,17). 

Diphtheria and Tetanus Toxoids and Pertussis Waccine Mdsorbed, USP Package Insert, Coimaught Laboratodes, Surftuster, Pa., revised 1994. 

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

Pertussis toxin (from Bordetella pertussis) [70323-44-3J Mr 117,000. Purified by stepwise elution from 3 columns comprising Blue Sepharose, Phenyl Sepharose and hydroxylapatite, and SDS-PAGE [Svoboda et al. Anal Biochem 159 402 1986, Biochemistry 21 5516 79[Pg.557]

Pertussis toxin Gj,0 proteins ADP-ribosylation Inhibition ofG protein signaling (whooping cough)... 

Functionally, the Dl-like receptors (Dl, D5) are coupled to the G protein Gas and thus can stimulate adenylyl cyclase. The D2-like receptors (D2, D3, and D4) couple to pertussis toxin sensitive G proteins (Gai/0), and consequently inhibit adenylyl cyclase activity. While the Dl-like receptors almost exclusively signal through Gas-mediated activation of adenylyl cyclase, the D2-like receptors have been reported to modulate the activity of a plethora of signaling molecules and pathways. Many of these actions are mediated through the G(3y subunit. Some of these molecules and pathways include the calcium channels, potassium channels, sodium-hydrogen exchanger, arachidonic acid release, and mitogen-activated protein kinase pathways. 

The ETa receptor activates G proteins of the Gq/n and G12/i3 family. The ETB receptor stimulates G proteins of the G and Gq/11 family. In endothelial cells, activation of the ETB receptor stimulates the release of NO and prostacyclin (PGI2) via pertussis toxin-sensitive G proteins. In smooth muscle cells, the activation of ETA receptors leads to an increase of intracellular calcium via pertussis toxin-insensitive G proteins of the Gq/11 family and to an activation of Rho proteins most likely via G proteins of the Gi2/i3 family. Increase of intracellular calcium results in a calmodulin-dependent activation of the myosin light chain kinase (MLCK, Fig. 2). MLCK phosphorylates the 20 kDa myosin light chain (MLC-20), which then stimulates actin-myosin interaction of vascular smooth muscle cells resulting in vasoconstriction. Since activated Rho... 

The OP group of receptois share common effector mechanisms. All receptois couple via pertussis toxin-sensitive Go and Gi proteins leading to (i) inhibition of adenylate cyclase (ii) reduction of Ca2+ currents via diverse Ca2+ channels (hi) activation of inward rectifying K+ channels. In addition, the majority of these receptors cause the activation of phospholipase A2 (PLA2), phospholipase C 3 (PLC 3), phospholipase D2 and of MAP (mitogen-activated protein) kinase (Table 3). 

Pertussis toxin is produced by the bacterium Bordetella pertussis. It covalently modifies G-proteins of the G/Go family (transfer of a ADP-ribose moiety of NAD onto G-protein a-subunits). ADP-ribosylated G-proteins are arrested in their inactive state and, as a consequence, functionally uncoupled from their respective effectors. Examples for pertussis toxin-sensitive cellular responses include the hormonal inhibition of adenylyl cyclases, stimulation ofK+ channels, inhibition of Ca2+ channels and stimulation ofthe cGMP-phosphodiesterase in retinal rods. 

The 3 isozymes are activated by G protein-coupled receptors through two different mechanisms [2]. The first involves activated a-subunits of the Gq family of heterotrimeric G proteins (Gq, Gn, Gi4, G15/16). These subunits activate the (31, (33 and (34 PLC isozymes through direct interaction with a sequence in the C terminus. The domain on the Gqa-subunit that interacts with the (3 isozymes is located on a surface a-helix that is adjacent to the Switch III region, which undergoes a marked conformational change during activation. The second mechanism of G protein activation of PLC 3 isozymes involves (3y-subunits released from Gi/0 G proteins by their pertussis toxin-sensitive activation by certain receptors. The 3y-subunits activate the 32 and 33 PLC isozymes by interacting with a sequence between the conserved X and Y domains. 

Vaccine diphtheria and tetanus toxoids and acellular pertussis adsorbed, hepatitis B (recombinant) and inactivated poliovirus combined Pediarix Active immunization against diphtheria, tetanus, pertussis and all known subtypes of hepatitis B virus, and poliomyelitis immunization Sfee adverse reactions against individual vaccines. Primary immunization series 3 doses of 0.5 mLat 6-to 8-week intervals IM (first dose is 2 months of age, but may be given as early as 6 weeks of age)... 

Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP). The... 

General interventions, such as increasing the fluids in the diet, allowing for adequate rest, and keeping the atmosphere quiet and nonstimulating, may be beneficial. The primary health care provider may prescribe acetaminophen, every 4 hours, to control these reactions. Local irritation at the injection site may be treated with warm or cool compresses, depending on the patient s preference. A lump may be palpated at the injection site after a diphtheria, pertussis, tetanus (DPT) injection or other immunization. This is not abnormal and will resolve itself within several days to several months. 

Bacterial Macromolecules. I. The Isolation of Deoxyribonucleic Acid from Virulent and Avirulent Strains of Haemophilus pertussis, W. G. Overend, M. Stacey, M. Webb, and J. Ungar, Paper presented at A. G. M., Soc. Gen. Microbiol., April 5, 1950. 

Secondly, treatment of neutrophils with pertussis toxin, which ADP-ribosylates a neutrophil G protein and causes a loss of cell responsiveness via receptor-mediated pathways (40,41), has minimal effect on the response to HCH (Figure 11, lower panel). Thus it can be concluded that HCH activation of neutrophils is independent of receptor-mediated activation of G proteins. 

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