Hepatitis A Vaccine

In the United States, the hepatitis A virus causes an estimated 75 000 to 125 000 cases of acute hepatitis each year, resulting in 100 deaths and incurring estimated costs of $200 million [2]. The virus is spread by the fecal-oral route, including through food or water contaminated by feces, and its incubation period averages 28 days (range, 2 to 7 weeks). The virus does not cause chronic hepatitis or a persistent carrier state. Children are the major reservoir of the virus, but adults bear the brunt of the clinical disease [3, 4] and are the focus of the current recommendations for hepatitis A vaccine. Subclinical infection is common, particularly in children. Among persons with reported cases of hepatitis A, the most commonly identified risk factors are personal contact with a person who has hepatitis A (26%), employment in or attendance at a day care center (14%), a history of injection drug use (11%), a history of recent international travel (4%), and association with a suspected food-borne or water-borne outbreak (3%) [5]. Of all persons with reported cases, 42% have no known risk factor.

The hepatitis A vaccine (HAVRIX, SmithKline Beecham Biologicals, Philadelphia, Pennsylvania) is a killed, formalin-inactivated vaccine prepared from whole virus grown in human diploid cells. Another similarly prepared vaccine is expected to be released in the near future (VAQTA, Merck, West Point, Pennsylvania). All studies to date indicate that these vaccines are highly immunogenic. The adult dose (1440 ELISA units) is 4 times the dose used in children and in adolescents less than 18 years of age. Specifically, 80% to 90% of adults given a single 1440-ELISA unit dose of vaccine have protective levels of antibody after 15 days, and more than 96% seroconvert after 30 days [6]. When a booster dose is given 6 or more months after the initial dose, essentially 100% of recipients develop high antibody levels. Two large, prospective pediatric studies show the efficacy of the hepatitis A vaccines. In a double-blind, randomized, controlled efficacy trial [7] involving 40 119 children in Thailand, half of whom received the vaccine, the calculated efficacy of HAVRIX in preventing clinical hepatitis was 94% (95% CI, 74% to 98%). In a trial of VAQTA [8], which involved children living in a closed religious community in Monroe, New York, clinical efficacy was 100% 21 days after immunization. In outbreak settings in several Alaskan villages, a rapid decrease in the number of cases of hepatitis A occurred after a single dose of vaccine was given to approximately 70% of susceptible individuals who were 2 to 20 years of age [9]. Protective efficacy studies have not been done in adults. No data have been reported on the use of hepatitis A vaccine in pregnant women or immunocompromised persons, including persons with the acquired immunodeficiency syndrome (AIDS).

Pre-exposure immunization with hepatitis A vaccine is recommended for adults in the following groups: 1) persons [including military personnel] traveling to or working in countries in which the hepatitis A virus is endemic; 2) homosexual men; 3) illicit drug users; 4) persons with chronic liver disease; and 5) persons with an occupational risk for infection, such as laboratory workers who handle live hepatitis A virus. Although epidemiologic data do not definitively support a recommendation to routinely immunize other occupational groups, such as day care workers, food handlers, and the staff of institutions for the developmentally challenged, the vaccine recommendations are permissive in allowing such persons to be immunized. When outbreaks have occurred in these occupational settings, the role of hepatitis A vaccine in outbreak control has not been evaluated. The aggressive use of immune globulin is the mainstay of post-exposure management.

Hepatitis A vaccination in adults requires a 1-mL intramuscular injection of the adult formulation (1440 ELISA units). A booster dose is given 6 to 12 months later to persons who need long-term protection. All studies to date [6] indicate an exceptional safety profile for these vaccines. Among adults, side effects have consisted of injection site soreness with some headache and malaise occurring within 2 days of administration.

Active immunization with the hepatitis A vaccine should greatly reduce the use of immune globulin in travelers. However, compared with hepatitis A vaccine, immune globulin is inexpensive, and it is a reasonable alternative for the traveler who plans a single visit to an area in which the virus is endemic but who does not need long-term protection. For the traveler who receives a first dose of hepatitis vaccine immediately before traveling, the administration of immune globulin may be considered in order to provide passive immunity during the 2 to 4 weeks before active vaccine-induced immunity develops. In this situation, the low dose (2 mL) of immune globulin should be used, because it does not have the marked depressive effect on antibody response to hepatitis A vaccine that has been seen with high-dose (5 mL) immune globulin [10, 11].

Varicella Vaccine

Although chickenpox (varicella) is primarily an infection of children, approximately 10% of adults in the United States are susceptible to it [12]. Compared with children, adults who contract varicella are at increased risk for pulmonary and central nervous system complications. Pregnancy and immunocompromised states are also associated with increased severity of illness [13, 14]. Although primary infection with varicella-zoster virus appears to confer lifetime immunity against subsequent varicella, the virus persists latently in the sensory nerve ganglia and may reactivate, causing herpes zoster. Overall, about 15% of adults develop herpes zoster [15], but the frequency and severity of the disease are greatly increased among immunocompromised or elderly persons.

Varicella vaccine (VARIVAX, Merck) was licensed for use in the United States in March 1995 after extensive testing both in the United States and abroad. It is a live, attenuated virus vaccine prepared from the Oka strain of varicella-zoster virus, which was first isolated in Japan in the early 1970s. The vaccine has been used widely in Europe and Japan for almost a decade; more than 2 million doses have been given since 1989 in Japan and Korea, and no serious safety problems have been identified.

In the United States, varicella vaccine has been studied in more than 9000 healthy children and more than 1500 adolescents and adults [16-18]. Immunogenicity in children has been consistently good after a single dose, with seroconversion rates of 95% or more. In adolescents (older than 13 years of age) and adults, the seroconversion rate was 78% after the first dose, and it increased to 99% after a second dose was given 4 to 8 weeks later. Antibody levels have persisted for at least 1 year in adults given two doses of vaccine (Merck. Unpublished data).

Vaccine Safety

About 15% of children developed fevers (oral temperatures of 102 °F) during the 6-week period after vaccination, usually in association with intercurrent illness. Injection site symptoms were reported in almost 20% of recipients, and about 7% of recipients developed a mild varicella-like rash, either localized at the injection site or generalized, with only a few skin lesions.

Transmission of vaccine virus to susceptible contacts from healthy children with varicella-like rash after immunization is uncommon, but, in children with leukemia, the frequency of this rash increases to about 17%, and transmission to susceptible siblings has been reported. The secondary cases, however, are subclinical or mild [19].

In uncontrolled trials done in adults given two doses of vaccine 4 to 8 weeks apart, febrile illness occurred during the subsequent 6 weeks after each dose in about 10% of vaccinated persons (Merck. Package insert). Between 25% and 33% of recipients had injection site symptoms, such as soreness, swelling, erythema, induration, or rash. After the first dose of vaccine, 3% of recipients developed an injection site rash with a median of two lesions, and 5% developed diffuse rash with a median of five lesions. The number of vaccine-associated rashes decreased sharply with the second dose of vaccine. Transmission of varicella-zoster virus from adults who developed varicella-like rash after vaccination has not been studied.

The incidence of herpes zoster in vaccinated children has been estimated to be 18 per 100 000 person-years of follow-up (Merck. Unpublished data), a rate believed to be lower than that found in children after natural varicella. One case of zoster has been reported among the adults given the vaccine, producing an incidence of 13 per 100 000 person-years. All cases of zoster were mild and without complications. Although vaccine virus has usually been recovered from vaccinated patients with zoster, wild virus has been found in a few cases, suggesting that some cases may be due to previous natural varicella infection.

Clinical Effectiveness

In a controlled trial in children, vaccine efficacy was estimated to be 95% as many as 7 years after immunization [20]. Controlled efficacy trials have not been done in adults. Attack rates among vaccinated children after household exposure have been reduced by up to 75% or more, and the severity of disease has been markedly reduced in vaccinated compared with unvaccinated children [18, 20]. Importantly, the transmission of varicella-zoster virus to susceptible siblings from vaccinated persons who developed breakthrough varicella has been sharply reduced.

The pediatric varicella-zoster virus vaccine studies indicate that this vaccine provides 70% to 90% protection against infection and 95% protection against severe disease for 7 to 10 years after vaccination, but this vaccine is less effective than certain other live, attenuated viral vaccines, such as that for measles. Manufacturer's data indicate that household exposure to varicella within 5 years after vaccination resulted in clinical varicella in 20% of exposed, previously vaccinated children and 27% of exposed, previously vaccinated adolescents and adults. The disease in these cases was mild, however, and usually had fewer than 50 skin lesions.

Indications

Although the primary target for varicella vaccine is infants and children, the vaccine is approved for use in susceptible adolescents and adults because of the increased severity of varicella in older age groups.

Persons with a reliable history of previous varicella may be assumed to be immune [21, 22]. Even 75% or more of adults without a reliable history of varicella will prove to be immune by sensitive antibody assays such as the latex agglutination test, which has good sensitivity and specificity and is relatively inexpensive [23]. Serologic testing before vaccination of adults who do not have a reliable history of varicella is probably cost-effective. However, there is no harm in vaccinating, inadvertently or not, persons who are immune.

We recommend varicella vaccination for susceptible adolescents and adults in the following target groups, listed in order of priority: 1) health care workers; 2) susceptible household contacts of immunocompromised persons; 3) persons living or working in environments with a high risk for varicella-zoster virus transmission, such as schools and day care centers; 4) young adults in closed or semiclosed populations, such as college students and members of the military; 5) nonpregnant women of childbearing age [this will reduce the risk for perinatal or congenital varicella]; 6) international travelers [immunity may be important for international travelers who anticipate close personal contact with local populations]; and 7) other susceptible adolescents or adults.

Special Considerations for Health Care Workers

We recommend that all physicians and health care institutions 1) implement programs to screen all health care workers by history and, if appropriate, by serologic test results and 2) immunize all persons susceptible to varicella. Persons exposed to varicella-zoster before this program is completed and whose immune status is unknown should be managed using existing institutional infection control guidelines. If these persons are susceptible to varicella and fail to develop it, they would then be candidates for vaccination. The protective effect of vaccination of susceptible persons after exposure is unknown. Vaccinated persons who are exposed to varicella should be tested for seropositivity immediately after exposure. Persons with detectable antibody are unlikely to develop varicella; persons lacking antibody may be retested in 5 to 6 days to determine whether an anamnestic response has occurred. Those who remain susceptible should be placed on leave, and the institution's existing infection control guidelines for varicella exposure should be followed.

Additional information on the risk for transmission of vaccine virus from persons with varicella-like rash after vaccination is needed. This risk, if it exists, appears to be low and is clearly outweighed by the benefits of vaccinating susceptible health care workers. We believe that the manufacturer's package insert is excessively cautious about the risk of immunizing health care workers, and we urge physicians and health care institutions to vigorously pursue programs to ensure varicella immunity for all health care personnel.

Vaccine Administration

Adolescents and adults should be given two 0.5-mL doses subcutaneously; the second dose should be given 4 to 8 weeks after the first. The vaccine is lyophilized and must be stored frozen at – 5 °F to – 4 °F (– 15 °C to – 20 °C). When reconstituted as recommended, the vaccine must be used within 30 minutes; vaccine not used within 30 minutes should be discarded.

Precautions and Contraindications

The early focus of varicella vaccine development was on protecting immunocompromised children from severe primary infection. The vaccine has been shown to be well tolerated, immunogenic, and protective in children with acute lymphoblastic leukemia in remission [24], and it is available from the manufacturer for persons who meet protocol eligibility standards. However, the vaccine is not licensed for use in immunocompromised persons pending further studies.

The effects of vaccine virus on fetuses are unknown, and pregnant women should therefore not be vaccinated. Nonpregnant women who receive vaccine should defer pregnancy for 1 month after receiving each dose. However, natural varicella infection poses only a small risk to the fetus, and thus vaccination during pregnancy, even during the first trimester, would not ordinarily be a sufficient reason to interrupt the pregnancy.

Unresolved Issues

This is the first live vaccine directed against a viral infection known to possess the property of latency, and many issues are unresolved. For example, are booster doses of the vaccine necessary to maintain immunity, and, if they are, how often should they be given? If the vaccine is universally used in children, as has been recommended, will the age-specific incidence of varicella shift toward young or older adults, as occurred with measles? Will this result in more cases of severe varicella in adults, and would the vaccine strategy thus need to include the universal vaccination of all adolescents or young adults, or both? Will the circulation of wild varicella virus decrease so sharply that adult populations, whose immunity may frequently be boosted by exposure to wild varicella virus, become paradoxically more susceptible? What will be the herpes zoster experience in 40 years of children who receive varicella vaccine today? Finally, will giving the vaccine to elderly adults decrease the frequency or the severity of herpes zoster?

The last question of these questions is already being studied in a long-term trial of varicella vaccine in healthy elderly patients who had varicella in the past. The other questions can only be answered by long-term surveillance of varicella in the United States for the next several decades after varicella vaccine use becomes widespread.

Purified Typhoid Vi Polysaccharide Vaccine

In the United States, approximately 500 cases of typhoid fever occur annually, mostly among travelers to or from countries in which typhoid is endemic [25, 26]. Although typhoid vaccine is not required for entrance into these countries, the availability of safe and effective vaccines should motivate the physician to provide this worthwhile preventive measure for patients traveling to these areas. The emergence of ampicillin and chloramphenicol-resistant strains of Salmonella typhi in these countries should also encourage immunization.

The newly introduced purified typhoid Vi polysaccharide vaccine (Vi CPS) contains the capsular or cell surface Vi (virulence) polysaccharide antigen, but it lacks the cell wall components that are responsible for the endotoxin reactions commonly observed with the other parenteral typhoid vaccines. A single intramuscular injection of 25 µg of the new vaccine produces seroconversion in 95% of healthy U.S. adults (the older parenteral vaccines require two doses for primary immunization to achieve similar seroconversion rates) [26]. Although no direct comparisons of the typhoid vaccines have been made, the efficacy of the new vaccine in field trials done in children is similar to that observed with the other typhoid vaccines (range, 51% to 77%).

Adverse reactions to Vi CPS are minimal, and, in pediatric trials, this vaccine caused fewer local or systemic reactions than did the meningococcal or pneumococcal vaccines [27, 28].

The single dose for primary immunization and the favorable adverse reaction profile establish Vi CPS as the preferred parenteral typhoid vaccine for adults (Table 1). Physicians and patients still have the option of using the oral, enteric-coated, live-attenuated vaccine made from the Ty 21a strain of S. typhi (Vivotif Berna, Swiss Serum and Vaccine Institute, Bern, Switzerland) [26]. This vaccine offers protection similar to that of Vi CPS but requires compliance with a four-dose regimen over 7 days. A complex set of conditions must be observed, including refrigeration (but not freezing) of the capsules; ingestion 1 hour before meals; and ingestion with cool liquid. The patient may not be immunocompromised or receiving antibiotics or mefloquine. Therefore, except in the patient who is severely averse to injections, Vi CPS will usually be the preferred typhoid vaccine.

No data have been reported on the use of any of the typhoid vaccines in pregnant women or immunocompromised persons, including persons with AIDS, but the parenteral Vi CPS is theoretically the safer alternative. Data are scanty about the need for booster doses in persons who have renewed or continuous exposure to S. typhi. Currently, the manufacturers of Vi CPS recommend booster doses at 2-year intervals, whereas the recommendation for the oral TY 21a vaccine is that reimmunization (four doses) be done at 5-year intervals (Table 1).

The recommendations for typhoid immunization remain unchanged and focus on travelers to developing countries, household contacts of S. typhi carriers, and persons who frequently work with S. typhi in laboratories.

Pneumococcal and Influenza Vaccines

Although the implementation of adult immunization recommendations remains poor by pediatric standards, significant progress has been made in recent years. The National Health Interview surveys [29] indicate that, currently, slightly more than one half of targeted persons are receiving influenza vaccine and that approximately one fourth of targeted persons have received pneumococcal vaccine. These immunization rates are approximately double those of a decade ago and prevent an estimated 5000 deaths annually from influenza and pneumococcal infections. More than one third of persons 50 to 64 years of age have risk factors that are indications for influenza and pneumococcal immunization (Table 2). The current implementation of vaccine recommendations is particularly poor in this age group. The American College of Physicians Task Force for Adult Immunization has strongly recommended that age 50 years be established as a time for review of preventive health measures with special emphasis on evaluating risk factors that would indicate a need for pneumococcal vaccine and the initiation of annual influenza immunization [1]. The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention has adopted this as national policy [30]. Strategies to reach the Public Health Service adult immunization goals for the year 2000 (60% of all elderly and high-risk persons should have received influenza and pneumococcal vaccine) have been proposed [31]. Efforts to improve influenza vaccine implementation have been aided by studies showing that influenza immunization in currently targeted groups has strong economic and medical benefits [32, 33] and that immunizing young and healthy persons may also have economic benefits [34]. Managed care protocols and greater attention to capturing immunization opportunities (at the time of hospitalization or other health system contact) should also spur further improvements.

Dr. Eickhoff: Division of Infectious Disease, University of Colorado Health Sciences Center, Denver, CO 80262.

Dr. Poland: Department of Medicine and Clinical Pharmacology, Mayo Vaccine Research Group, Mayo Clinic and Foundation, Rochester, MN 55905.

Dr. Gross: Department of Internal Medicine, Hackensack Medical Center, Hackensack, NJ 07601.

Dr. Griffin: Departments of Preventive Medicine and Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-5305.

Dr. LaForce: The Genesee Hospital, University of Rochester School of Medicine and Dentistry, Rochester, NY 14607.

Dr. Schaffner: Department of Preventive Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, TN 37232-2637.

Dr. Strikas: National Immunization Program, Centers for Disease Control and Prevention, Atlanta, GA 30333.