Evaluation of the safety, reactogenicity and immunogenicity of FluBlok® trivalent recombinant baculovirus-expressed hemagglutinin influenza vaccine administered intramuscularly to healthy adults 50-64 years of age.

BACKGROUND: Alternative methods for influenza vaccine production are needed to ensure adequate supplies. METHODS: Healthy adults 50-64 years were assigned randomly to receive one intramuscular injection of trivalent recombinant hemagglutinin (rHA) or U.S. licensed trivalent inactivated vaccine (TIV) containing H1, H3 and B antigens (Ag) derived from 2007 to 2008 influenza virus strains A/Solomon Islands/03/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004. Each rHA dose contained 45 µg HA/strain of the 2007-2008 FDA-recommended Ag vs. 15 µg/strain for TIV. Antibody (Ab) responses were measured using a hemagglutination-inhibition (HAI) assay at baseline and 28 days post-vaccination. Respiratory samples for viral culture were collected from subjects with influenza-like illness (ILI) during the 2007-2008 season in the U.S. RESULTS: 601 subjects were enrolled. Vaccines were well tolerated. Seroconversion (the percentage of subjects with either (a) a pre-vaccination HAI titer ≤ 10 and a post-vaccination HAI titer ≥ 40 or (b) a pre-vaccination titer ≥ 10 and a minimum four-fold rise in post-vaccination HAI antibody titer) in the TIV and rHA groups, respectively, was obtained in 66% vs. 72% for H1; 44% vs. 61% for H3; and 41% vs. 41% for B. Proportions achieving titers ≥ 40 were 96% vs. 96% for H1, 75% vs. 85% for H3, and 94% vs. 93% vs. B. Geometric mean titer ratios at day 28 (TIV/rHA) were 0.77 for H1; 0.58 for H3; and 1.05 for B, respectively. ILI frequencies were low and similar in both groups. CONCLUSIONS: Both vaccines were safe and immunogenic. Ab responses vs. H1 and H3 Ags were significantly higher in the rHA group, with similar responses to B. Furthermore, the FluBlok group had a statistically significantly higher seroconversion rate against influenza A/H3N2 compared to the TIV group.

Comparative immunogenicity of recombinant influenza hemagglutinin (rHA) and trivalent inactivated vaccine (TIV) among persons > or =65 years old.

Alternative substrates for influenza vaccine production are needed to ensure adequate supplies. We evaluated the relative safety and immunogenicity of recombinant hemagglutinin (rHA) or trivalent inactivated vaccine (TIV) among 869 > or =65-year-old subjects in a randomized clinical trial. Virologic surveillance for influenza-like illness (ILI) was conducted during the 2006-2007 epidemic. Vaccines were well tolerated. Seroconversion rates vs. influenza A/H1N1 and H3N2 antigens were superior in the rHA group, but were inferior vs. influenza B; however, results for influenza B are confounded since the vaccine antigens were different. ILI frequencies were low and similar in both groups. Studies assessing relative immunogenicity of vaccines using identical B Ags are warranted.

Report of a US public health service workshop on hypotonic-hyporesponsive episode (HHE) after pertussis immunization.

Hypotonic-hyporesponsive episode (HHE) is a term used to describe a somewhat heterogenous group of clinical disorders that have been reported primarily in association with whole-cell pertussis vaccination. A 1991 review by the Institute of Medicine determined that the evidence available was indeed consistent with a causal relation between whole-cell pertussis-diphtheria-tetanus immunization and HHE, but that the evidence was insufficient to indicate a causal relationship between HHE and the subsequent development of permanent neurologic damage. More recent data from clinical trials conducted in Europe suggest that HHE also occurs after vaccination with acellular pertussis vaccines. The US Food and Drug Administration, in collaboration with the US Public Health Service, sponsored a workshop on HHE in Rockville, Maryland, on June 19, 1997. The primary goals of the workshop were to develop a case definition of HHE and to evaluate the general design and feasibility of possible studies of HHE using the federal Vaccine Adverse Event Reporting System (VAERS), a national passive surveillance system. The goals of such studies would be to understand better the acute HHE event and to evaluate the possibility of long-term sequelae. Case Definition. There has been no generally accepted definition of HHE, and a standard definition would be useful for vaccine safety work and would potentially facilitate interstudy comparisons of the growing number of licensed vaccines containing acellular pertussis components. The workshop defined HHE as an event of sudden onset occurring within 48 hours of immunization, with duration of the episode ranging from 1 minute to 48 hours, in children younger than 10 years of age. All of the following must be present: 1) limpness or hypotonia, 2) reduced responsiveness or hyporesponsiveness, and 3) pallor or cyanosis or failure to observe or to recall skin coloration. HHE is not considered to have occurred if there is a known cause for these signs (eg, postictal), if urticaria is present during the event, if normal skin coloration is observed throughout the episode, or if the child is simply sleeping. This inclusive (sensitive) case definition will allow investigators, through the technique of stratification according to certain characteristics (eg, time from vaccination to onset of HHE), to attempt to hone the definition and make it more specific. Refinement of the definition of HHE has been hindered by the lack of information on its pathophysiology and by the lack of pathognomonic signs, symptoms, and diagnostic tests. Another hindrance is that by the time the child presents for medical evaluation, the signs of HHE often have normalized. Moreover, different mechanisms may be involved in different individuals whose events meet this workshop's HHE definition. Further Study of HHE. Probably the most important question about HHE is whether it has any permanent sequelae. The workshop assessed the possible contribution VAERS-based studies could make to answering this question and found substantial methodologic problems; however, ongoing studies in Sweden and The Netherlands have the potential to provide useful information on this question. The most useful contribution of VAERS data would be in a descriptive study of HHE, with a possible case-control study of factors that may affect the risk of HHE after vaccination, rather than a study of possible permanent sequelae. The workshop participants felt that a detailed descriptive study of approximately 100 HHE events reported during a 1- to 2-year period could provide a more in-depth description of HHE cases in greater numbers than has been published previously, but the study would not address the issue of long-term sequelae of HHE. Better descriptive data may lead to new hypotheses concerning risk factors, etiology, and pathophysiology of HHE that might be evaluated further by studying subsequent cases and controls from VAERS or from other sources, depending on the hypoth

Influenza pandemic preparedness plan for the United States.

In preparation for the next influenza pandemic, a comprehensive and action-oriented plan is presently under development that focuses on six major areas: (1) improvements in ongoing virologic and disease-based surveillance systems; (2) vaccination of high-priority target groups, and, given sufficient vaccine supplies, the entire US population; (3) liability programs for vaccine manufacturers and health care providers; (4) research to improve detection of new variants and to accelerate the availability of existing and novel vaccines and antiviral agents; (5) integrated, multicomponent communication systems for rapid information dissemination and exchange; and (6) emergency preparedness plans to provide for adequate medical care and maintenance of essential community services. The sudden and unpredictable emergence of pandemic influenza and its potential for causing severe health and social consequences dictate the need for close collaboration among a wide variety of organizations in both the public and private sectors.

Syncope after immunization.

OBJECTIVE: To describe the individual characteristics, clinical features, and morbidity associated with syncope following immunization. DESIGN: Large case series. SETTING: United States, 1990 through 1995. SUBJECTS: Reports to the national Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system. An additional 3 reports of head injury (documented by medical records) were obtained through the National Vaccine Injury Compensation Program. MAIN OUTCOME MEASURES: Syncope, syncope and hospitalization, or syncope and head injury within 12 hours of vaccination. RESULTS: A total of 697 cases of syncope after vaccination was reported. Age younger than 20 years was reported for 77.4%; 57.5% were female. Hospitalization was reported in 9.6%. Of the 571 syncope events with known time, 511 occurred 1 hour or less after vaccination. Of these, 323 (63.2%) occurred 5 minutes or less, 454 (88.8%) occurred 15 minutes or less, and 500 (97.8%) occurred 30 minutes or less after vaccination. Tonic or clonic movements, which have been associated with the anoxia of vasovagal syncope, were reported in 30.4% of syncopal episodes occurring 15 minutes or less after and in 12.8% of those occurring 15 minutes or longer after vaccination (P < .001). Six patients suffered skull fracture, cerebral bleeding, or cerebral contusion after falls; 3 of these patients required neurosurgery. Falls occurred 15 minutes or less after vaccination, in or near the clinic or office. Ages ranged from 12 to 28 years; 5 of 6 were male. Follow-up revealed substantial residual impairment in 2 patients. CONCLUSIONS: Prevention of injury from syncope after vaccination and of syncope itself may be possible in many cases. Vaccinators should be aware that patients exhibiting presyncopal signs and symptoms around the time of immunization need to be evaluated carefully and may need to be assisted to sit or lie down after immunization until free of symptoms.

Outbreak of paralytic poliomyelitis in a highly immunized population in Jordan.

Between November 1991 and March 1992, 37 cases of paralytic poliomyelitis occurred in Jordan, where none had been reported since 1988. Of these, 17 (50%) of 34 patients had received at least three doses of oral poliovirus vaccine (OPV3). The first and 2 subsequent case-patients were children of Pakistani migrant workers, and the first 8 and a total of 27 (75%) case-patients resided in or near the Jordan Valley. A seroepidemiologic study of 987 children in all regions of Jordan was performed to assess OPV3 coverage and immune response to OPV. Although OPV3 coverage by 12 months of age was high (96%) in the general population, coverage was lower among Pakistani (21%), Bedouin (63%), and Gypsy (9%) children (P < .001). Seroprevalences for poliovirus type 3 were 71% in the Jordan Valley versus 81% in other regions after 3 doses of OPV (P < .06) and 77% in the Jordan Valley versus 98% in other regions after 5 doses of OPV (P < .001). This outbreak demonstrates the importance of achieving high seroimmunity to infection in all geographic areas to prevent the reintroduction and spread of imported strains of wild poliovirus.

Outbreaks of paralytic poliomyelitis, 1976-1995.

During 1976-1995, 48 outbreaks of paralytic poliomyelitis with a cumulative total of approximately 17,000 cases were reported worldwide. Outbreaks occurred on most continents, affected from 0.1 to 52 persons per 100,000 total population (median, 4.4), lasted 2-25 months (median, 7), typically involved unvaccinated or inadequately vaccinated subgroups within highly immunized communities, and were primarily caused by poliovirus type 1 (74%). Cases in developing countries occurred predominantly among children <2 years of age, while those in industrialized countries tended to occur in older persons who had escaped natural infection earlier in life and who had not been vaccinated or had received poliovirus vaccine of inadequate potency. Partial genomic sequencing studies indicated that at least 15 outbreaks resulted from importation of wild polioviruses, primarily from the Indian subcontinent. These findings illustrate the potential for wide dissemination of wild poliovirus infection and underscore the critical need for maintaining high levels of immunity in all countries and for more aggressive vaccination efforts in areas in which polio is endemic.

Increased immunogenicity of oral poliovirus vaccine administered in mass vaccination campaigns compared with the routine vaccination program in Jordan.

To compare the immunogenicity of routine versus mass campaign doses of oral poliovirus vaccine (OPV), serum neutralizing antibodies were measured in 254 children before and after two mass vaccination campaigns in Jordan. Precampaign seroprevalences to poliovirus types 1, 2, and 3 in children who had received three, four, or five routine doses of OPV were compared with postcampaign seroprevalences in children who had received one, two, or three routine doses plus two mass campaign doses. Seroprevalences were consistently higher in subgroups that received two doses through mass campaigns than in subgroups that received all doses through the routine program, especially for poliovirus type 3. Geometric mean titers were also consistently higher for mass campaign subgroups, particularly for poliovirus type 3. The findings suggest that adding further doses of OPV to the routine schedule is unlikely to have as great an impact on the immune state of children as administering the same number of doses during mass campaigns.

Humoral and mucosal immunity in infants induced by three sequential inactivated poliovirus vaccine-live attenuated oral poliovirus vaccine immunization schedules. Baltimore Area Polio Vaccine Study Group.

The relative immunity induced by sequential administration of inactivated poliovirus vaccine (IPV) produced in human diploid cells and live attenuated oral poliovirus vaccine (OPV) was evaluated by randomization of 510 infants to receive IPV and OPV sequentially according to one of three experimental schedules, IPV only, or OPV only. The antibody response to two IPV doses was lower than expected. However, for each of the IPV-OPV sequential schedules, the first OPV dose significantly enhanced seroconversion rates and geometric mean microneutralization antibody titers. Three months after the final dose, 96%-99%, 99%-100%, and 81%-100% of infants had antibodies to poliovirus types 1, 2, and 3, respectively, and subjects with two or more prior OPV doses were significantly less likely than those with none or one prior OPV dose to excrete virus in feces after an OPV challenge. Sequential IPV-OPV immunization is now recommended for routine use in the United States. The optimal schedule consists of two IPV doses followed by two OPV doses.

The effect of diarrhea on oral poliovirus vaccine failure in Brazil.

The effect of diarrhea on oral poliovirus vaccine (OPV) failure was evaluated using data from Brazil, where 728 infants were immunized at birth (OPV1) and approximately 6 (OPV2), 10 (OPV3), and 14 (OPV4) weeks. Recent diarrhea history was significantly associated with increased vaccine failure only after OPV2 for poliovirus types 2 and 3. In multivariate models, controlling for breast feeding, season of vaccine administration (type 3 only), maternal antibody (type 3 only), and immunization campaign exposure (type 3 only) strengthened this effect. Diarrhea at OPV receipt was associated with vaccine failure to poliovirus types 1 and 3 only after OPV2. These data support the current recommendation that children with diarrhea receive OPV and be reimmunized once their illness resolves. Expanding this recommendation to include children with a recent diarrhea history should be considered. While the effect of diarrhea on vaccine failure may be limited to OPV2, programmatic realities may preclude dose-specific recommendations.

Seroprevalence of antibody against poliovirus in inner-city preschool children. Implications for vaccination policy in the United States.

OBJECTIVES: To assess susceptibility to poliomyelitis in selected inner-city preschool children in the United States and to estimate the contribution of secondary spread of live attenuated oral poliovirus vaccine virus to type-specific immunity. DESIGN: Cross-sectional seroprevalence study. METHODS: Serum neutralizing antibody levels against poliovirus types 1, 2, and 3 were analyzed according to vaccination status, age, and other sociodemographic variables. SETTING: Hospital and satellite clinics serving inner-city populations in Houston, Tex, and Detroit, Mich, 1990 to 1991. PARTICIPANTS: A total of 526 children aged 12 to 47 months seeking medical care were enrolled in the seroprevalence study; 144 children aged 12 to 35 months without a history of previous oral poliovirus vaccination were enrolled in the secondary spread study. RESULTS: Seropositive rates were similar in children in both cities, ranging from about 80% for types 1 and 3 in 12- to 23-month-old children to more than 90% in those aged 36 to 47 months. The most important predictor of seropositivity was the number of doses of oral poliovirus vaccine received (P < .01), with levels approximately 90% for all 3 serotypes among children who had received 3 or more doses. In children likely to have been unvaccinated, seropositive rates ranged from 9% to 18% for poliovirus types 1 and 3 and from 29% to 42% for type 2; secondary spread of vaccine virus appeared to have occurred among children who had previously received 1 dose or less but not those with 2 or more doses. CONCLUSIONS: Levels of immunity to poliovirus among inner-city preschoolers are high and may be predicted by the number of doses of oral poliovirus vaccine received. Secondary spread of the vaccine virus plays a modest role in increasing polio immunity in inner-city populations, especially against types 1 and 3. This role will decrease in importance if the recently attained high levels of immunization coverage in the United States are sustained and if the risk of importation of wild poliovirus continues to diminish.

Changing levels of measles antibody titers in women and children in the United States: impact on response to vaccination. Kaiser Permanente Measles Vaccine Trial Team.

OBJECTIVES: In the United States, younger women are more likely to have immunity to measles from vaccination and are less likely to have been exposed to the wild virus than are older women. To evaluate changes in measles antibody titers in women in the United States and children's responses to measles vaccination, we analyzed data from a measles vaccine trial. METHODS: Sera collected from children before vaccination at 6, 9, or 12 months of age and from their mothers were assayed for measles antibodies by plaque reduction neutralization. Responses to vaccination with Merck Sharp & Dohme live measles virus vaccines at 9 months (Attenuvax) and 12 months (M-M-R II) were also analyzed. RESULTS: Among women born in the United States (n = 614), geometric mean titers (GMTs) of measles antibodies decreased with increasing birth year. For those born before 1957, 1957 through 1963, and after 1963, GMTs were 4798, 2665, and 989, respectively. Among women born outside of the United States (n = 394), there were no differences in GMTs by year of birth. Children of younger women born in the United States were less likely than those of older women to be seropositive at 6, 9, or 12 months. The response to the vaccines varied by maternal birth year for children of women born in the United States. Among 9-month-old children, 93% of those whose mothers were born after 1963 responded, compared with 77% and 60% of those whose mothers were born in 1957 through 1963 and before 1957, respectively. Among 12-month-old children, 98% of those born to the youngest mothers responded, compared with 90% and 83% of those whose mothers were born in 1957 through 1963 and before 1957. The responses of children of women born outside of the United States were not associated with maternal year of birth. CONCLUSIONS: An increasing proportion of children in the United States will respond to the measles vaccine at younger ages because of lower levels of passively acquired maternal measles antibodies.

Evaluation of house-to-house versus fixed-site oral poliovirus vaccine delivery strategies in a mass immunization campaign in Egypt.

Among poliomyelitis eradication activities recommended by WHO are national immunization days. Most campaigns have delivered oral poliovirus vaccine (OPV) from fixed sites, reaching 80-90% of target populations. Although house-to-house vaccination provides nearly universal coverage, countries have been reluctant to use this approach because it is considered more costly and logistically difficult. To quantify the cost-effectiveness of both these strategies, we compared the vaccine coverage and vaccination costs per child for house-to-house and fixed-site delivery (38% and 13% higher, respectively), the costs per child vaccinated were similar. This was due primarily to the high coverage levels achieved in house-to-house delivery (100% versus 86%) and the reduced vaccine wastage. Vaccinating children at highest risk of infection was only 25-50% as expensive on a per child basis using house-to-house delivery, since such children were less likely to visit fixed sites. These findings may not be generalizable to other countries where labour costs are higher and the population density lower; however, house-to-house delivery may prove to be the most cost-effective eradication strategy by ensuring universal access to immunization.

PIP: In a 1993 mass immunization campaign in Egypt, the vaccine coverage rate and per child vaccination costs were compared for house-to-house versus fixed-site oral poliovirus vaccine (OPV) delivery. House-to-house delivery achieved 100% OPV coverage, compared to about 86% for fixed-site delivery (p 0.01). The cost for house-to-house vaccination was 25% higher than for fixed-site vaccination in urban areas, while they were similar in rural areas. Regardless of delivery approach, the cost of vaccine made up around 75% of the total cost of the campaign. In urban areas, the cost per child vaccinated was similar for both fixed-site and house-to-house vaccinations ($0.11). In rural areas, it was higher for fixed-site delivery than for house-to-house delivery ($0.14 vs. $0.11). Costs of fixed-site delivery for children who received either zero or 1 dose of OPV prior to the campaign were around 2-4 times higher than those of house-to-house delivery in both urban and rural areas. OPV wastage for both delivery approaches was the same (around 25%) in urban areas, while it was much higher for fixed-site vaccination than for house-to-house vaccination (41.5% vs. 23.5%). For fixed-site vaccinations, the youngest and oldest children, children with less than 3 OPV doses, and children without vaccination cards were less likely to be vaccinated than their counterparts (p 0.01). These findings suggest that, in Egypt, house-to-house delivery may be the most cost-effective strategy to achieve universal coverage and thus to eradicate polio.