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Chapter: Medical Immunology: The Humoral Immune Response and Its Induction by Active Immunization

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Types of Vaccines

A wide variety of immunizing agents has been developed. The following are some examples of the types of immunizing agents that are used for immunoprophylaxis in humans.

Types of Vaccines

A wide variety of immunizing agents has been developed. The following are some examples of the types of immunizing agents that are used for immunoprophylaxis in humans.

 

1. Killed Vaccines

Killed vaccines are generally safe, but they are not as effective as attenuated vaccines.

1.           Killed bacteria include the traditional pertussis vaccine prepared with killed Bor-detella pertussis, the etiological agent of whooping cough, the typhoid vaccineprepared with acetone-inactivated Salmonella typhi, and the cholera vaccine, prepared with killed Vibrio cholerae. The killed B. pertussis vaccine was re-ported to cause neurological reactions similar to autoallergic encephalitis, par-ticularly in children with a history of neonatal or postnatal seizures. However, these reactions are extremely rare and were mostly observed in Great Britain.

 

2.           Inactivated viruses include the influenza vaccine, the hepatitis A vaccine, and Salk’s polio vaccine. The inactivated poliovaccine contains a mixture of the three known types of poliovirus, after inactivation with formalin. This vaccine has been as successful in the eradication of poliomyelitis as Sabin’s attenuated oral vaccine. Its main advantage is safety, but it is not as effective or amenable to mass immunizations as the oral vaccine . However, safety con-cerns have resulted in its wider use in countries where poliomyelitis has been vir-tually eradicated, and there is greater risk of contracting polio from the attenu-ated vaccine than from a wild virus strain.

 

2. Component Vaccines

 

Component vaccines are even safer than killed vaccines, but their efficacy can be problematic.

Bacterial Polysaccharides.Bacterial polysaccharides, such as those used for Streptococcus pneumoniae, Neisseria meningitidis, andHaemophilus influenzae type b,and for a typhoid fever vaccine made of the Vi capsular polysaccharide. Because of their T-independent nature, polysaccharide vaccines are not very potent (especially in young children) and do not elicit long-lasting memory .

Inactivated Toxins.Inactivated toxins (toxoids), such as tetanus and diphtheriatoxoids, which are basically formalin-inactivated toxins, have lost their active site but maintained their immunogenic determinants. Toxoids are strongly immunogenic proteins and induce antibodies able to neutralize the toxins. The response to toxoids is associated with long-lasting memory.

Recombinant Bacterial Antigens.Recently, a recombinantRickettsia rickettsiiantigen produced in E. coli has been proposed as a candidate vaccine for Rocky Mountain spotted fever. Recombinant toxoids (e.g., recombinant pertussis toxin) have also been in-troduced in human vaccines. These differ from classical toxoids in that they are produced by genetically engineered organisms to which an altered gene coding for an inactive toxin (toxoid) has been introduced.

Mixed Component Vaccines.The interest in developing safer vaccines forwhooping cough led to the introduction of acellular vaccines. These are constituted by a mixture of inactivated pertussis toxin or recombinant pertussis toxin (nontoxic due to the deletion of critical domains), a major determinant of the clinical disease, and one or several adhesion factors, which mediate attachment to mucosal epithelial cells. These vaccines have replaced the old vaccine prepared with killed Bordetella pertussis.

Conjugate Vaccines.Most polysaccharide vaccines have shown poor immuno-genicity, particularly in infants. This lack of effectiveness is a consequence of the fact that polysaccharides tend to induce T-independent responses with little immunological mem- ory. This problem appears to be eliminated if the polysaccharide is conjugated to an im-munogenic protein, very much like a hapten-carrier conjugate.

The first conjugate vaccines to be developed involved the polyribositolribophosphate (PRP) of Haemophilus influenzae type b (Hib). Four conjugate vaccines have been suc-cessfully tested, the first three being currently approved by FDA:

1.           PRP-OMPC, in which the carrier is an outer membrane protein complex of Neis-seria meningitidis

 

2.           Hib-OC, in which the carrier (OC) is a nontoxic mutant of diphtheria toxin

 

3.           PRP-T, in which the carrier is diphtheria toxoid

 

The introduction of these vaccines was followed by a 95% decrease in the incidence of H.influenzae type b infections affecting children younger than 5 years of age.

A conjugate vaccine prepared with the capsular polysaccharides of the seven most common types of Streptococcus pneumoniae has received FDA approval for use in the pe-diatric population, and a conjugate vaccine for Neisseria meningitidis is currently being evaluated.

Viral Component Vaccines.Viral component vaccines are based on the immuno-genicity of isolated viral constituents. The best example is the hepatitis B vaccine, produced by recombinant yeast cells. The gene coding for the hepatitis B surface antigen (HBsAg) was isolated from the hepatitis B virus and inserted into a vector, flanked by promoter and terminator sequences. That vector was used to transform yeast cells, from which HBsAg was purified. All the available hepatitis B vaccines are obtained by this procedure.

Some of the proposed HIV vaccines are component vaccines, constituted by enve-lope glycoproteins (gp160 or its fragment, gp120) or peptides derived from these glyco-proteins, produced in genetically engineered E. coli, insect cells, and mammalian cell lines. These vaccines have not been proven to induce protective immunity .

Synthetic Peptide Vaccines.The use of synthetic peptides for vaccination has theadvantages of easy manufacture and safety. The goal is to synthesize the peptide sequences corresponding to known epitopes recognized by neutralizing antibodies and use them as vaccines. This theoretically appealing concept meets with two basic problems. First, it is highly questionable that a synthetic oligopeptide has the same tertiary configuration as the epitope expressed by the native antigen and that protective antibodies can be elicited in this manner. However, if the objective is to induce cell-mediated immunity, this may not be an insurmountable obstacle. Second, small synthetic peptides are poorly immunogenic. The use of peptide-protein (e.g., tetanus toxoid) conjugates can minimize this problem.

The most promising work with synthetic peptide vaccines has been carried out with Plasmodium peptides. In a murine malaria model, immunization with a tetanustoxoid–Plasmodium berghei peptide conjugate resulted in rates of protection ranging from 75 to 87%, identical to those observed with a killed vaccine made of the whole parasite. In humans, efforts have been concentrated on the development of a vaccine against Plasmod-ium falciparum. A multirepeat region (approximately 40 repeats of the sequence Asn-Ala-Asn-Pro) of the circumsporozoite protein was identified as the immunodominant B-cell epitope and used as a model for a peptide-based vaccine. However, the rate of protection obtained in the first trials with this vaccine was too low (two out of nine subjects immu-nized were protected), probably because of differences in tertiary structure between the synthetic peptide and the Plasmodiumepitope.

DNA Vaccines.The observation that intramuscular injection of nonreplicating plas-mid DNA encoding the hemagglutinin (HA) or nucleoprotein (NP) of influenza virus elicited humoral and cellular protective reactions attracted enormous interest from the scientific com-munity. The recombinant DNA is taken up and expressed by APCs at the site of injection and is presented to T-helper cells in a way that both humoral and cell-mediated immune responses are elicited. The safety and easy storage of candidate DNA vaccines are extremely appealing and several different trials are ongoing. However, the initial impression from human trials is that DNA vaccines are far less potent in humans than they appear to be in experimental ani-mals. At this point is too early to pass judgment on the practical value of DNA vaccines.

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