Adequate response to immunization is most frequently judged by measuring the development of specific serum immunoglobulins (e.g., antibodies) following a course of administration of vaccine. The concentration of specific immunoglobulin in plasma is usually proportional to the degree of protection from the viral agent. However, the relation between immunologic response to a vaccine and protection afforded by it to subsequent disease must be documented in field trials. The longevity of the protective response must always be determined to establish the most appropriate interval for revaccination.
Eradication
Although the widespread use of antibiotics has had little success in curtailing the prevalence of bacterial infection, and in certain instances has resulted in the appearance of resistant pathogens of potentially greater harm, the success of vaccines in reducing incidence of disease has been remarkable. Lack of success has been largely related to the socioeconomic problems preventing distribution of the vaccine. When these problems have been appropriately solved, eventual eradication of some diseases has become possible. Certain favorable epidemiologic characteristics of smallpox made it an ideal candidate to eradicate. These include the following:
- Humans are the only known host.
- Smallpox is an acute disease with a short incubation period.
- Immunity following infection is relatively long lasting and effective.
- There is only one antigenic strain of virus.
- Subclinical infections are rare.
- Epidemic patterns are seasonal.
- A successful vaccine is available.
Unfortunately, these characteristics are not widely shared by other pathogens. Thus, successful eradication will probably be limited to a small number of diseases. Wild-type poliovirus infection has been eradicated from the Western hemisphere and efforts continue toward global eradication. It has been agreed that measles irradication is technically possible, and a goal of 2005 to 2010 has been set (CDC 1997a).
| Table Routine Vaccines for Humans | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Table Schedule for Active Immunization of Normal Infants and Children | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Adverse effects of vaccines
Adverse effects of vaccines vary and are often related to the method of preparation of the vaccine (i.e., the cell culture system in which the vaccine has been prepared).
Hypersensitivity reactions are too frequently the consequence of inadequate attempts to obtain a detailed history or inattention to the appropriate necessary precautions (e.g., adequate preliminary testing before administration). The clinician is advised to consult local state health officials regarding updated precautions for adverse effects associated with vaccination before immunization. Nonliving vaccine products require a much larger antigenic mass (dose) and more frequent booster injections than do live vaccines to provide adequate levels of protection. This is exemplified by the requirement for multiple boosters of immunization against diphtheria, tetanus, and pertussis, compared with the single administration required for live mumps virus vaccine. The larger doses and repeated administration required for nonliving vaccines may lead to higher rates of allergy and other reactions. During the developmental trials of two killed vaccines (measles vaccine and respiratory syncytial virus vaccine), production of a hypersensitivity state ensued that, while not preventing infection, produced an exaggerated host response to subsequent natural infections resulting in a clinically unusual and more severe disease than was previously seen.
Hypersensitivity reactions have led to some contraindications to vaccinations. Recent studies have shown that egg allergy should no longer be a contraindication to measles/mumps/rubella vaccine. Canadian authorities no longer recommend the delay of vaccination for measles/mumps/rubella in children with egg allergy (Canadian National Advisory Committee 1996). Egg allergy remains a contraindication for both influenza and yellow fever vaccines as the method of vaccine preparation is different from measles/mumps/rubella vaccine and these vaccines contain higher concentrations of ovalbumin. Vaccine preservatives and additives, including thimerosal (a mercurial preservative), neomycin, and aluminum have been implicated in hypersensitivity reactions but rarely in anaphylactic reactions.
Although attenuated live-virus vaccines may more effectively mimic natural infection in stimulating host defenses, they can be made in such a way that there is a risk of inadequate attenuation of the virus or of the virus reverting to a less attenuated form. Thus, the full-blown disease may appear following vaccination. Immunosuppressed patients are at higher risk of developing vaccine-associated infections. Both oral live-attenuated polio virus vaccine and live measles vaccine have been implicated in such complications. Furthermore, since these live-virus vaccines do not go through a process of harsh inactivation before administration, the risk of introducing dangerous adventitious agents into the host is increased. For example, certain animal tumor viruses that contaminated tissue culture support systems in some of the early vaccines were inadvertently introduced into recipients. Fortunately, careful follow-up of cohorts of these recipients has failed to show any increased rates of neoplasia.
The administration of vaccines to pregnant women presents a special problem. In this situation, the probable risk of maternal (and fetal) infection must be balanced against the known adverse effects of vaccination. Adequate immunization against tetanus is essential for both mother and child, and tetanus toxoid immunization is safe during pregnancy. Immunization against poliomyelitis and yellow fever is indicated in pregnant women traveling to epidemic areas. Other live vaccines, including measles, mumps and rubella are generally contraindicated during pregnancy because of the risk of infecting the fetus.
PRINCIPLES
With the development and introduction of each new vaccine, the physician must balance the seriousness of the disease being prevented against the known and unknown risks involved in widespread use of the vaccine. Prophylaxis with vaccine is warranted only in populations threatened by significant morbidity and mortality from the disease, in whom likely benefits outweigh possible risks.
Poliomyelitis: A disease illustrating the principles of immunotherapy
Poliomyelitis is a disease caused by infection with one of three types of poliovirus, a member of the enterovirus group. These viruses are transmitted by both the oral-fecal and respiratory routes, the latter being of lesser importance. Colonization and multiplication of the virus take place in the lymphatic tissue of the oropharynx and bowel. Dissemination occurs thereafter via the regional lymphatics and by viremia. After dissemination, the tissue tropism that allows the poliovirus to multiply within the lower motor neurons of the spinal cord becomes apparent. The injury to these lower motor neurons is responsible for the most devastating clinical manifestations of paralytic polio. Host defenses include the elaboration of local antibody (IgA) in the gastrointestinal tract and type-specific humoral antibodies that can be detected in the circulation. When present, the latter antibodies indicate that the host is protected against reinfection. There is no cross-protection between the three types of poliovirus.
The clinical manifestations of poliomyelitis appear 1 to 3 weeks after exposure to the virus and appear to be related to age. The overwhelming majority of cases in children are completely asymptomatic (90%). Those persons who do have symptoms usually have a mild fever, headaches, some mild gastrointestinal symptoms, and occasionally a sore throat. In contrast to adolescents and adults, young children rarely have involvement of the central nervous system. When they develop, neurologic symptoms usually appear from 2 to 6 days after the initial illness. The neurologic involvement (1% of infected individuals) is primarily lower motor neuron disease that results in flaccid paresis.
Hematologic and biochemical tests usually are within normal limits except for the findings in the cerebrospinal fluid, respiratory secretions, and feces. These samples should be taken as early as possible in the course of the disease to increase the likelihood of successful isolation of the virus. Paired samples of sera showing a fourfold or greater rise in type-specific antibody against polio virus are diagnostic of the disease.
There is no acceptable antiviral chemotherapy for an established case of poliomyelitis. Treatment in this instance is entirely supportive and aimed at preventing other infections and reversing or preventing the biochemical or respiratory problems related to the neurologic destruction caused by the disease. The development and application of polio vaccine provide one of the most successful stories in modern therapeutics. Before the introduction of polio vaccine in 1954, recurrent epidemic polio with significant rates of neurologic disease plagued industrialized societies. Nonindustrialized societies usually had their infections during childhood, with very low rates of neurologic disease. As public health measures improved, the oral-fecal spread of polio virus shifted to an older population more prone to neurologic involvement. This natural history has been repeated in developing societies up to the present. With the use of either the Salk killed vaccine (IPV) or the Sabin oral polio vaccine, this disease has been reduced to rare occurrences in unvaccinated groups. The Western hemisphere documented the last case of wild-type polio virus infection in 1979.
In recent years, outbreaks of poliomyelitis have been associated with pockets of unvaccinated persons, importation of wild-type virus from endemic areas, and lower than optimal vaccination rates. National Immunization Day mass campaigns in developing countries have been adopted to further decrease the annual rates of wild-type infections. In the United States, an average of 10 cases of polio virus infection are reported yearly, all of them vaccine-associated strains. Developed countries must not become complacent regarding vaccination as the emergence of susceptible groups of unvaccinated persons provides the opportunity for reemergence of infection and severe disease.
Recent additions to vaccination recommendations
New formulations of vaccines have recently been marketed to increase immunogenicity at an earlier age and to decrease potential adverse effects. Conjugate H. influenzae b vaccine (HbCV), acellular pertussis vaccine, and recombinant hepatitis B vaccine are examples. H. influenza until recently was the most common cause of childhood meningitis in the United States with a death rate of 1 to 5%. Early formulation of the vaccine was effective only in children greater than 18 months of age. Newer H. influenza conjugate vaccines with inactive diphtheria toxin, outer-membrane protein complex of group B meningococcus, and tetanus toxoid as their protein carrier can be given to children ≤2 months. Combination formulations with diphtheria/tetanus/pertussis vaccine make scheduling easier. Whole-cell pertussis vaccine developed in the 1940s was considered 70 to 90% effective in early trials. More recent trials estimated efficacy as low as 36 to 48%.
Adverse events were commonly associated with whole-cell pertussis vaccine, prompting the development of acellular pertussis vaccine. This formulation contains inactivated pertussis toxin and one or more other bacterial components. Clinical trials with combination diphtheria, tetanus, and acellular pertussis (DTaP) vaccines showed efficacy of 59 to 89%, with feweradverse events than the original diphtheria/tetanus/pertussis vaccine formulation. Recommendations for primary immunization and booster vaccination of pertussis encourage the use of DTaP.
Recombinant hepatitis B vaccine has replaced the pooled human sera vaccine. This has eliminated the risk of blood-borne organism transmission through vaccination while providing an effective agent for the prevention of hepatitis B. Efforts are under way to improve the efficacy of the pneumococcal vaccine. Presently the 23-valent polysaccharide vaccine is not immunogenic in infants and is poorly so in immunodeficient hosts. Protein conjugate vaccines similar to HbCV vaccines are undergoing phase III trials with some preliminary hopes of reducing pneumococcal carriage, otitis media, and invasive pneumococcal infections.
Immunization of immunosuppressed host
Individuals with immunodeficient states, including human immunodeficiency virus, hematological malignancy, transplant recipients, congenital deficiencies, or underlying illnesses such as diabetes and renal and liver failure, are at increased risk of severe morbidity from some preventable infections. Routine childhood immunization should be performed in these individuals with exception of live vaccines. Haemophilus type b, pneumococcal, and influenza vaccines are recommended in these patients, and they should be offered hepatitis B and meningococcal vaccines if indicated. Live vaccines such as measles or oral polio vaccine are contraindicated in patients with severe immunodeficiency, as their risk of acquired vaccine-related infection is too high. Oral polio vaccine is also contraindicated in household members of patients with severe immunodeficiency states (CDC 1994a).
Immunization for the traveler
Increase in business and pleasure international travel has seen an increase in risk of acquisition or importation of infectious diseases endemic in many developing countries. Many of these infections can be avoided by preventative measures and education (hand-washing, eating only adequately cooked food, insect repellents, and proper clothing), and others can be prevented by obtaining the appropriate vaccines long enough before travel for them to be effective. Routine vaccinations should be completed or updated before departure. Additional vaccines which are often necessary include hepatitis A, hepatitis B (now available as a combination hepatitis A and B vaccine), meningococcal, yellow fever, typhoid, and cholera vaccines. Although cholera vaccines are presently not generally recommended, new recommendations may come forth as oral cholera vaccine studies show adequate efficacy in large field trials. Local health authorities should be consulted for further information regarding immunizations required for destination.
Vaccines under development
As the incidence of genital herpes increases worldwide, the search for an effective vaccine continues. This vaccine must not only prevent primary herpes infection but also recurrent infections to decrease the pool of potentially infected individuals. Animal trials have been successful using genetically modified viruses. A randomized, controlled, double-blind placebo study of 2393 HSV-2 seronegative persons failed to show any protection in vaccinated individuals. Further trials are under way using modifications to this and other vaccines to assess efficacy.
Rotavirus is the leading cause of diarrheal illness in infants and young children less than 2 years of age. This infection leads to significant rates of hospitalizations in the Western world and severe morbidity and mortality in developing countries. Live attenuated rotavirus vaccines delivered by the oral route are under investigation. Joensuu et al. (1997) have assessed the efficacy of rhesus-human reassortant rotavirus tetravalent vaccine in a randomized, placebo-controlled trial of 2398 Finnish children. Overall vaccine efficacy was 66%, but of 100 cases of severe diarrheal illness, only 8 were in the vaccine group. It therefore appears that vaccination could lead to a decrease in severe rotavirus gastrointestinal disease.
Respiratory syncytial virus respiratory infections are responsible for hospitalization of 1% of infants in their first year of life and up to 3% mortality in infants with underlying lung or heart disease. Vaccination against Respiratory syncytial virus is a priority to diminish the morbidity and mortality it causes. Vaccine development has been problematic as natural infection confers only partial, temporary immunity, and initial vaccines caused an increase in severity of subsequent illness. The most promising vaccine to date is a purified preparation of the fusion protein of Respiratory syncytial virus which has undergone efficacy study in small groups of 18- to 36-month-old children. Infection rates were decreased compared with the placebo group over a 2-year period. For unclear reasons, infants have not responded immunologically as well to this vaccine. Finally, new advances are being made in immune therapeutics with the development of DNA vaccines. These use genes encoding proteins of pathogens or tumors to elicit a humoral or cell-mediated response. DNA vaccines for prevention of microbial infections are under development for influenza B and hepatitis B viruses, malaria, tuberculosis, and human immunodeficiency virus.
| Table Immunization for the Traveler | |||||||||||||||||||||||||||||||||||||||
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