Rotavirus vaccines--from licensure to disease reduction.

Rotavirus infection produces a serious health burden in the United States, causing an estimated > 100,000 hospitalizations and > 100 deaths annually. This health burden is comparable to that for measles, pertussis, mumps, and varicella before vaccines for these diseases were routinely given to children. Rotavirus vaccines have the potential to significantly reduce a serious public health problem in the United States. However, while development and licensure of vaccines is a major breakthrough, it represents only the first step in disease prevention. Vaccines must be recommended by major immunization advisory committees, financed in both the public and private sectors, and successfully integrated into the existing vaccination schedule. Vaccines must reach all targeted children, and monitoring systems must be established or adapted to better determine vaccine safety and disease impact. Reevaluation of disease prevention strategies must be ongoing and fueled by new information on safety and disease reduction.

Monitoring progress toward US preschool immunization goals.

The United States has achieved over 97% immunization of children by school age and has reduced the incidence of vaccine-preventable diseases by more than 90% since the prevaccination era. However, children often do not receive immunizations at the recommended age, and in densely populated urban areas this delay in immunization has led to epidemics of measles. Correctable deficiencies of the immunization delivery system have been identified in these areas. To respond to needs, the public health infrastructure must be strengthened, and active participation from the private sector must be obtained, both in delivery of immunizations and in assessment of performance. Appropriate action must be stimulated by the provision of timely information on immunization coverage and on indicators of program performance at the local level.

Mucosal immunity induced by enhance-potency inactivated and oral polio vaccines.

Oral polio vaccine (OPV) is recommended for routine immunization in the United States in part because of its ability to induce intestinal and pharyngeal immunity to reinfection. Mucosal immunity produced by OPV and enhanced-potency inactivated polio vaccine (E-IPV) was compared by challenging vaccines with type 1 OPV. Fewer OPV (25%) than E-IPV (63%) vaccinees excreted OPV virus in stool after challenge. The mean stool virus titer was higher and the duration of shedding longer among E-IPV excreters. Only one E-IPV and three OPV vaccinees shed virus in the pharynx after challenge. Prechallenge serum neutralizing antibody levels were not statistically different among E-IPV vaccinees who did and did not shed virus; these levels were much higher than those of OPV vaccinees. Poliovirus-specific IgA levels in stool did not correlate with viral excretion. E-IPV was less effective than OPV in preventing and limiting intestinal infection, even though it induced higher postvaccination serum antibody levels.

Surveillance. Information for action.

Success in immunization requires success in developing an adequate information base. While special studies are important, there is no substitute for surveillance systems. Such systems help evaluate health impact, monitor trends in reported disease and adverse events, and identify areas for more intense investigation. Surveillance data alone have played major roles in immunization strategy changes. Successful surveillance relies on cooperation by health care providers and health departments. While filling out forms and reporting cases may be viewed as a burden by some, such information in the aggregate becomes an important part of the knowledge base used to refocus implementation efforts and potentially to change strategies. Reporting by all physicians is particularly important when reported cases lead to aggressive control actions such as outbreak control. Rapid reporting even when cases are not confirmed can help health departments ensure that needed laboratory specimens are collected and allow control measures to be undertaken before disease containment becomes difficult. In conclusion, any immunization program worth instituting is worth monitoring. Surveillance represents constant vigilance to ensure effective control or elimination of disease.

Immunization of six-month-old infants with different doses of Edmonston-Zagreb and Schwarz measles vaccines.

Because measles causes an estimated 2 million deaths per year among children in developing countries, including a substantial proportion of infants less than nine months old--the age at which vaccination is recommended--there has been interest in using different strains of vaccine and higher doses to achieve immunization of younger infants. We conducted a randomized trial of three different doses of Edmonston-Zagreb and of Schwarz measles vaccines in infants to evaluate the effect of the strain and dose of vaccine on the serologic response and acute adverse reactions to vaccination. Six-month-old infants received a standard, medium, or high dose of one of the vaccines, and nine-month-old infants received a standard dose. Antibody levels were measured before and after vaccination, by means of a plaque-reduction neutralization assay, in 1061 six-month-olds and 299 nine-month-olds. Edmonston-Zagreb vaccine produced higher rates of seroconversion and seropositivity than comparable doses of Schwarz vaccine. Among the six-month-old infants, the seroconversion rate 18 weeks after vaccination with the standard dose of Edmonston-Zagreb vaccine was 92 percent, that with the medium dose was 96 to 97 percent, and that with the high dose was 98 percent; the rates for the corresponding doses of Schwarz vaccine were 66 percent, 76 percent, and 91 percent, respectively. Higher seroconversion rates were observed with an increase in the dose of either Edmonston-Zagreb (P less than 0.01) or Schwarz (P less than 0.001) vaccine. The seroconversion rates produced by high and medium doses of Edmonston-Zagreb vaccine in six-month-olds were equal to or significantly higher than the rate produced by a standard dose of Schwarz vaccine in nine-month-olds (87 percent). Clinical adverse reactions were not associated with the strain or dose of a vaccine. We conclude that Edmonston-Zagreb vaccine is more immunogenic than Schwarz vaccine in infants and can induce effective immunization against measles at six months of age.

Barriers to vaccinating preschool children.

Immunization represents one of the most effective tools in preventive medicine. But despite what should be a universal practice, preschool children, particularly in the inner cities, are not being adequately vaccinated. The responsibility for low immunization levels does not rest solely with the parents. Major obstacles within the health care system provide disincentives to immunization. Local resource problems such as inadequate clinic staff, hours, and locations make immunizations difficult to obtain. When comprehensive care is not easily accessible (e.g., requiring appointments weeks or months in advance), policies which require immunization to take place only within such a setting are further barriers. Many opportunities for vaccination are lost when children interact with the health care system but do not receive all the immunizations they need. Policies must be changed to facilitate immunization and to take advantage of all health care visits to provide vaccines.

Rubella antibody persistence after immunization. Sixteen-year follow-up in the Hawaiian Islands.

A comparative field trial of three rubella virus vaccines (Cendehill, HPV-77 DE-5, and HPV-77 DK-12) was initiated in 1969 on the islands of Kauai and Hawaii in the state of Hawaii. In 1985, follow-up was reinitiated to assess the long-term durability of vaccine-induced immunity. Enzyme-linked immunosorbent assays of serum specimens from 1290 participants demonstrated seropositive rates of 92.4% and 96.4% at screening levels of 10 (protective level) and 7 (lowest detectable level) IU/mL, respectively. The seropositive rates were not related to reinfection or reimmunizations. These findings indicate that vaccine-induced rubella antibodies are detectable in almost all persons up to 16 years after successful vaccination.

Protective efficacy of a whole cell pertussis vaccine.

A trial of the efficacy of a plain whole cell pertussis vaccine was conducted in Sweden. In this non-blinded trial 525 infants aged 2 months who were born on days with an even number received three doses of vaccine one month apart and 615 infants of the same age who were born on days with an odd number were enrolled as controls. During the 18 months of follow up there were 55 cases of pertussis. The attack rate was 1.5% (8/525) among the vaccinated children and 7.6% (47/615) among the unvaccinated children (p less than 0.001). The estimated efficacy of the vaccine was 80% (95% confidence interval 58 to 90). The estimated efficacy of pertussis vaccine was similar to that observed in British trials over 30 years ago.

Immunization of young infants with Edmonston-Zagreb measles vaccine.

Recently studies conducted in several countries using Edmonston-Zagreb vaccine administered subcutaneously to infants younger than 9 months of age have shown high seroconversion rates, approaching or equaling those routinely achieved at 9 months of age with the more widely used Schwarz vaccine. These results have raised expectations that the Edmonston-Zagreb vaccine can play an important role in helping to prevent measles in young infants in highly endemic areas. Because of the implications of changing the measles vaccine recommendations, vaccine advisory groups and vaccine manufacturers will require additional studies to confirm the preliminary findings and to answer new questions which have been raised. The needed data will probably be collected over the next year or two in studies already under way or being planned in the hope that a more effective vaccine for young infants can be introduced before the end of this decade.

Acellular and whole-cell pertussis vaccines in Japan. Report of a visit by US scientists.

Since the introduction of acellular pertussis vaccines in Japan late in 1981, more than 20 million doses have been administered, mostly to children 2 years of age and older. Clinical studies indicate that mild local and febrile reactions are less frequent after administration of acellular pertussis vaccines than after whole-cell vaccines. Serious adverse events with sequelae occurred in 2-year-old children at approximately the same low rate during the period 1975 through August 1981, when whole-cell vaccines were used, and during August 1981 through 1984, when acellular vaccines were used exclusively. Five household contact studies have yielded vaccine efficacy estimates ranging from 78% to 92% in children 1 year of age or older. In addition, there has been a continuing decrease in reported pertussis incidence from the epidemic peak in 1979. Additional data on the safety and efficacy of acellular pertussis vaccines administered to infants would be useful in consideration of acellular pertussis vaccine licensure in the United States.

Impact of revaccinating children who initially received measles vaccine before 10 months of age.

Two hundred fifty-four infants who had received measles vaccine at less than 10 months of age were revaccinated at greater than or equal to 15 months of age, and their immune responses were compared with 129 control infants who received their first doses of measles vaccine at greater than or equal to 15 months of age. Sera were collected at the time of revaccination (study infants) or primary vaccination (control infants), 3 weeks, and 8 months later and tested for antibody by hemagglutination inhibition (HI), enzyme-linked immunosorbent assay (ELISA), and cytopathic effect neutralization (CPEN). Of the 121 study infants who were initially HI negative, 116 (95.9%) made HI antibody 3 weeks postrevaccination compared with 126 (99.2%) of 127 control infants (P = 0.19). Of the 63 study infants with no initial detectable antibody by any of the three tests, 14 (22.2%) had a measles-specific IgM response 3 weeks postrevaccination compared with 37 of 50 (74.0%) randomly chosen control infants. By 8 months after revaccination, the 121 initially HI-negative study infants were significantly less likely to have detectable HI antibodies than control infants (52.1% v 97.6%) (P less than .001). However, 96.7% of these 121 study infants had detectable neutralizing antibody 8 months postrevaccination, an antibody thought to correlate best with protection. This study confirms the altered immune response to revaccination in infants first vaccinated prior to 10 months of age; however, the data suggest that most of these infants were successfully primed and are probably protected after revaccination.

Field evaluation of vaccine efficacy.

PIP: This paper describes the epidemiological techniques available for measuring vaccine efficacy and recommends a practical approach to their use. The efficacy of vaccines in clinical use can be determined by a variety of means, including screening, outbreak investigations, secondary attack rates in families or clusters, vaccine coverage assessment, and case-control studies. They all offer a means of monitoring vaccine programs under conditions of day-to-day vaccine use. A table summarizes the different techniques for measuring efficacy. The screening technique is the most useful and rapid means of determining whether there is a problem with a vaccine. All that is required is a reliable estimate of the proportion of cases occurring in vaccinated individuals and an estimate of the vaccine coverage in the population at risk. If the estimated efficacy is within expected limits, more detailed studies are not warranted. If the results suggest low efficacy, more rigorous methods are necessary to assess the efficacy more accurately. Of the more accurate methods available, outbreak investigation offers the simplest means of measuring vaccine efficacy and is the preferred technique if the situation permits. The biases inherent in the method can be minimized, particularly if the disease incidence rate is high during the outbreak and accurate records exist. In large populations, the underlying immunization status prior to the outbreak can be estimated using the same cluster sampling method used in coverage assessments. Calculation of secondary attack rates in families is also an excellent and accurate means of measuring vaccine efficacy and is an acceptable alternative to the outbreak investigation. Vaccine coverage methods in endemic areas are best suited to urban areas where the measles incidence rate is high after age 11 months and low before 12 months, and maternal histories of disease are thought to be accurate. Case-control studies are best suited to areas where reliable personal immunization records may be difficult to find but other information, such as clinic records, may be available. No epidemiological method is perfect because it cannot exactly duplicate the experimental conditions of a prospective randomized clinical trial. The most accurate results will be obtained when biases are anticipated and corrective measures are taken whenever possible. Clinical vaccine efficacy determinations are carried out in order to assess whether the observed pattern of illness is consistent with the proper use of a highly effective vaccine. The components of a vaccine efficacy evaluation -- case definition, case ascertainment, and vaccination status determination -- apply to studies on all vaccines.^ieng