Interim within-season estimate of the effectiveness of trivalent inactivated influenza vaccine--Marshfield, Wisconsin, 2007-08 influenza season

During clinical trials, the efficacy of vaccination with inactivated influenza vaccines for the prevention of serologically confirmed influenza infection has been estimated as high as 70%-90% among healthier adults. However, the effectiveness of annual influenza vaccination typically is lower during those influenza seasons when a suboptimal match between the vaccine strains and circulating influenza strains is observed. For example, in a 4-year randomized study of influenza vaccine among healthy persons aged 1-65 years, the predominant strain was drifted from the vaccine strain in 2 of the 4 years. Inactivated vaccine effectiveness (VE) against culture-confirmed influenza ranged from 71% to 79% when the vaccine and circulating strains were suboptimally matched to 74% to 79% when the matches were well matched. In contrast, a 2-year study of inactivated influenza vaccine among healthy adults aged 18-64 years found no measurable VE during a year when a poorly matched strain circulated, but found VE of 86% against laboratory-confirmed influenza during the following year when the vaccine and circulating strains were well matched. Although laboratory data on the antigenic characteristics of circulating influenza viruses compared with vaccine strains are available during influenza seasons, estimates of VE usually have not been made until months after the conclusion of the season. This report summarizes interim results of a 2008 case-control study to estimate the effectiveness of trivalent inactivated influenza vaccine for prevention of medically attended, laboratory-confirmed influenza during the 2007-08 influenza season, when most circulating influenza A (H3N2) and B viruses were suboptimally matched to the vaccine strains. Despite the suboptimal match between two of three vaccine strains and circulating influenza strains, overall VE in the study population during January 21-February 8, 2008, was 44%. These findings demonstrate that, in any season, assessment of the clinical effectiveness of influenza vaccines cannot be determined solely by laboratory evaluation of the degree of antigenic match between vaccine and circulation strains.     

Estimating influenza vaccine effectiveness in an outbreak when anti-viral medications were used as a control measure

OBJECTIVES: To estimate influenza vaccine effectiveness (VE) from an outbreak of influenza A in an aged care facility in which neuraminidase inhibitors were used as part of outbreak control measures. METHODS: The outbreak occurred between 25 December 2001 and 21 January 2002. Neuraminidase inhibitors were used to control the outbreak. Residents and staff with respiratory symptoms were tested for influenza using RT-PCR and/or serology. Vaccine effectiveness (VE) was estimated for the prevention of laboratory-confirmed influenza. RESULTS: Nineteen of 42 (45%) residents and four of 29 (14%) staff were laboratory-confirmed as cases. The outbreak was caused by an influenza A (H3N2) strain, antigenically matched to that season's vaccine. The VE for preventing laboratory-confirmed influenza infection was 61% (95% CI 41-73) among residents and 100% (95% CI 63-100) among staff. CONCLUSIONS: The VE estimates calculated from this outbreak were consistent with other published results. Outbreaks of influenza in institutions provide a good opportunity to review influenza VE, but use of antiviral medications as control measures may affect interpretation of findings.     

Influenza vaccine effectiveness among 50-64-year-old persons during a season of poor antigenic match between vaccine and circulating influenza virus strains: Colorado, United States, 2003-2004

During the 2003-2004 influenza season, we conducted a case-control study of influenza vaccine effectiveness (VE) among Colorado residents aged 50-64 years. Cases (n=330) were identified from laboratory-confirmed influenza reports to the Colorado Department of Public Health and Environment (CDPHE). Controls (n=1055) were recruited by random-digit dial telephone survey. VE was 60% (43-72%) and 48% (21-66%) among those without and with high-risk medical conditions, respectively. VE was 90% (68-97%) and 36% (0-63%) against influenza-related hospitalization for persons without and with high-risk conditions, respectively.     

Concurrent and cross-season protection of inactivated influenza vaccine against A(H1N1)pdm09 illness among young children: 2012–2013 case–control evaluation of influenza vaccine effectiveness

In 2012–2013, we examined 1729 laboratory-confirmed A(H1N1)pdm09 influenza cases matched 1:1 with healthy controls and estimated influenza vaccine effectiveness (VE) for trivalent inactivated influenza vaccine (IIV3) to be 67% (95% confidence interval = 58–74%) for ages 8 months to 6 years old. Among children aged 8–35 months old, VE for fully vaccinated children (73%, 60–81%) was significantly higher than VE for partially vaccinated children (55%, 33–70%). Significant cross-season protection from prior IIV3 was noted, including VE of 31% (8–48%) from IIV3 received in 2010–2011 against influenza illness in 2012––2013 without subsequent boosting doses.     

Effectiveness of the 2003-2004 influenza vaccine among U.S. military basic trainees: a year of suboptimal match between vaccine and circulating strain

Effectiveness of the 2003-2004 influenza vaccine was evaluated at five military basic training centers throughout the United States. Data from surveillance conducted in December and January 2003-2004 in this highly vaccinated population were evaluated. During this period, 10.6% (37/350) of specimens were positive for influenza A. A 14-day period after vaccination was considered the period prior to immune protection; vaccine effectiveness (VE) was calculated based on febrile respiratory illness presentation and laboratory confirmation of influenza before or after this 14-day period. Thirty-two cases presented within 14 days of vaccination, and five cases presented beyond 14 days from vaccination. VE in this population was estimated to be 94.4% for laboratory-confirmed influenza. In contrast, VE was only 13.9% for influenza-like illness (ILI) without a laboratory confirmation.     

The effectiveness of influenza vaccination in preventing hospitalisation in children in Western Australia

BackgroundThere is increasing evidence demonstrating influenza vaccine effectiveness (VE) in the prevention of influenza in children, including the very young. Data demonstrating the effectiveness against severe disease, including hospitalisation, are limited. We aimed to determine the VE of the southern hemisphere trivalent inactivated influenza vaccine (TIV) in preventing laboratory-confirmed influenza-associated hospitalisation in children.Patients and MethodsLaboratory records were used to identify children with confirmed influenza hospitalised (i.e., cases) during a 5 year period (2008, 2010–2013) at the only tertiary paediatric facility in Western Australia. Cases and time, age and ward matched controls were retrospectively reviewed to determine risk factors, vaccination status and outcome. Adjusted odds ratios and VE estimates were derived using conditional logistic regression models.ResultsThree hundred and eighty five cases were identified (Influenza A, 64.9%; Influenza B, 35.1%). Influenza-like illness and pneumonia were the most frequent presentation (74.5% and 23.9%, respectively). The median length of stay was 2 days (Interquartile range 1–4 days). Twenty children (5.2%) required admission to the intensive care unit. Vaccine uptake in cases and controls was low (4.9% and 8.5%, respectively). Three hundred and six case-control pairs were included in the VE analysis, of which 19 pairs were informative with discrepant vaccination status. VE (fully vaccinated vs. unvaccinated) was estimated to be 62.3% (95% CI: −6.6%, 86.7%).ConclusionIn this study, the point estimate for the effectiveness of TIV in preventing influenza-associated hospitalisation in children was similar to that reported for emergency or outpatient attended, laboratory-confirmed influenza, yet confidence intervals were wide. Vaccine uptake remains low. Studies, enroling larger numbers of children, ideally with higher vaccine uptake, are needed to provide additional evidence on TIV protection against influenza hospitalisation in children.     

Effectiveness of seasonal influenza vaccine in Australia, 2015: An epidemiological,antigenic and phylogenetic assessment

BackgroundA record number of laboratory-confirmed influenza cases were notified in Australia in 2015, during which type A(H3) and type B Victoria and Yamagata lineages co-circulated. We estimated effectiveness of the 2015 inactivated seasonal influenza vaccine against specific virus lineages and clades.MethodsThree sentinel general practitioner networks conduct surveillance for laboratory-confirmed influenza amongst patients presenting with influenza-like illness in Australia. Data from the networks were pooled to estimate vaccine effectiveness (VE) for seasonal trivalent influenza vaccine in Australia in 2015 using the case test-negative study design.ResultsThere were 2443 eligible patients included in the study, of which 857 (35%) were influenza-positive. Thirty-three and 19% of controls and cases respectively were reported as vaccinated. Adjusted VE against all influenza was 54% (95% CI: 42, 63). Antigenic characterisation data suggested good match between vaccine and circulating strains of A(H3); however VE for A(H3) was low at 44% (95% CI: 21, 60). Phylogenetic analysis indicated most circulating viruses were from clade 3C.2a, rather than the clade included in the vaccine (3C.3a). VE point estimates were higher against B/Yamagata lineage influenza (71%; 95% CI: 57, 80) than B/Victoria (42%, 95% CI: 13, 61), and in younger people.ConclusionsOverall seasonal vaccine was protective against influenza infection in Australia in 2015. Higher VE against the B/Yamagata lineage included in the trivalent vaccine suggests that more widespread use of quadrivalent vaccine could have improved overall effectiveness of influenza vaccine. Genetic characterisation suggested lower VE against A(H3) influenza was due to clade mismatch of vaccine and circulating viruses.     

2013-2014年度季节性流行性感冒疫苗对儿童保护效果的病例对照研究

目的 评价2013-2014年度季节性流行性感冒疫苗（流感疫苗）对6~59月龄儿童的保护效果。方法 选择2013-2014年度6~59月龄的实验室诊断流感病例为病例组,在广州市免疫规划系统中随机选择健康儿童为对照组,进行成组病例对照研究,采用非条件Logistic回归计算保护效果。结果 本研究共纳入2 690名研究对象。2013-2014年度,流感疫苗对6~59月龄儿童的保护效果为42.3%（95% CI:27.8%~53.8%）,对36~59月龄儿童的保护效果高于6~35月龄儿童,完全免疫的保护效果高于部分免疫,性别间保护效果无统计学差异。结论 流感疫苗对6~59月龄儿童具有中等保护效果,建议6~59月龄儿童每年接种流感疫苗。     

Effectiveness of quadrivalent influenza vaccination in the first year of a funded childhood program in Queensland,Australia, 2018

BackgroundFollowing high influenza activity in 2017, the state of Queensland, Australia, funded a quadrivalent inactivated influenza vaccination program for children aged 6 months to <5 years in 2018. We calculated influenza vaccine effectiveness (VE) among children eligible for this program.MethodsA matched case-control study was conducted. Cases were identified using Queensland 2018 influenza notification data among children age-eligible for funded vaccination. Controls were drawn from Australian Immunisation Register records of Queensland resident children age-eligible for funded influenza vaccine. Up to 10 controls per case were matched for location and birthdate. First dose vaccination was valid if received ≥14 days prior to specimen collection; a second dose was valid if received ≥28 days after first dose receipt. VE was calculated for vaccine doses and adherence to national recommendations for two doses in the first season (schedule completeness) and adjusted (VE_adj) for sex and First Nations status.ResultsThere were 1,125 cases and 10,645 matched controls analysed. Overall VE_adj against laboratory-confirmed influenza was 51% (95% confidence interval (CI) 41–60). VE_adj was 60% (95% CI 46–70) for children who received two doses in 2018, and 60% (95% CI 48–69) for children vaccinated appropriately according to schedule completeness. VE increased with age.ConclusionsModerate vaccine effectiveness was observed for children eligible for the funded program in Queensland in 2018, adding to the sparse evidence for influenza vaccine use in Australian children. Adhering to the national first season two dose schedule for influenza vaccine receipt in children ensures maximum protection.     

Influenza vaccine effectiveness against laboratory-confirmed influenza in a vaccine-mismatched influenza B-dominant season

BackgroundThe 2017–2018 influenza season in Israel was characterized by the predominance of influenza B Yamagata, with a lesser circulation of influenza A(H1N1)pdm09 and influenza A(H3N2). We estimated vaccine effectiveness (VE) of the inactivated influenza vaccine which was selected for use that season.MethodsEnd-of-season VE and 95% confidence intervals (CI) against laboratory-confirmed influenza-like illness (ILI) were estimated by means of the test-negative design. Age-specific VE analysis was carried out using a moving age interval.ResultsSpecimen were obtained from 1,453 community ILI patients; 610 (42.0%) were influenza-positive, among which 69.7% were B, 17.2% A(H1N1)pdm09 and 13.4% A(H3N2). A 98.6% of molecularly characterized influenza B belonged to the Yamagata lineage. Of the sampled individuals, 1320 were suitable for VE analysis. Of those vaccinated, 90.6% received the inactivated trivalent influenza vaccine (TIV) containing a Victoria lineage influenza B-like virus. VE against influenza A differed by age, with the highest VE of 72.9% (95%CI 31.9–89.2%) observed in children 0.5–14 years old, while all ages VE was 46.6% (95%CI 10.4–68.2%). All ages VE against influenza B was 23.2% (95%CI −10.1–46.4%) with age-specific analysis showing non-significant VE estimates. Utilizing a moving age interval of 15 years, afforded a detailed age-specific insight into influenza VE against the influenza viruses circulating during the 2017–2018 season.ConclusionsThe moderate-high 2017–2018 influenza A VE among children and adolescents, supports seasonal influenza vaccination at a young age. The low VE against influenza B in Israel, is most likely the result of influenza B/TIV-mismatch.     

Estimating vaccine effectiveness against laboratory-confirmed influenza using a sentinel physician network: results from the 2005-2006 season of dual A and B vaccine mismatch in Canada

INTRODUCTION: We report a case-control design using a sentinel physician network to estimate vaccine effectiveness (VE) against laboratory-confirmed, medically attended influenza (LC-MAI) and provide results for the 2005-2006 season of dual A and B vaccine mismatch in Canada. METHODS: Participants were patients >or=5 years of age presenting with influenza-like illness (ILI) to a sentinel physician in British Columbia, Canada between November 1, 2005 and April 30, 2006. Cases were participants in whom influenza was identified; controls tested negative for influenza A and B by PCR, R-mix and culture. Isolates were characterized by gene-sequencing and hemagglutination-inhibition (HI) assays. Odds ratios (OR) for LC-MAI in vaccinated versus non-vaccinated persons were derived with adjustment for age and chronic conditions. VE was estimated as [1-OR (vaccinated/unvaccinated)]. RESULTS: The sample included 442 patient visits: median age was 26 years, 10% were >or=65 years, 15% had a chronic condition and 22% received the 2005-2006 trivalent inactivated influenza vaccine >or=2 weeks before ILI onset. Two hundred and six participants were positive for influenza; 107 (52%) had influenza A/H3N2 and 99 (48%) had influenza B/Victoria lineage. Gene sequencing identified mutations away from the vaccine strain at key antigenic binding sites of the hemagglutinin (HA) protein of H3N2 isolates; the neuraminidase (NA) protein was conserved. Based on HI assays, three-quarters of influenza A and all B isolates were mismatched to the 2005-2006 vaccine. Point estimates for VE against LC-MAI were in the range of 50 to 70% for both types of influenza. CONCLUSION: 2005-2006 was the third consecutive season of vaccine mismatch based on varying HA for the A/H3N2 component and the third also for the B component since 2001. Vaccine mismatch resulted in diminished VE but substantial cross-protection. More timely detection of drift variants through gene sequencing of isolates facilitates interpretation of VE results. Since it may be more antigenically conserved, the vaccine content and contribution of NA to overall VE should be further evaluated for both A and B components. Infrastructure for real-time epidemiologic assessment of vaccine performance is important annually and in preparation for a pandemic.     

Effectiveness of repeated influenza vaccination among the elderly population with high annual vaccine uptake rates during the three consecutive A/H3N2 epidemics

BackgroundAnnually, about 80% of the Korean elderly aged ≥65 years receive influenza vaccination. Repeated annual vaccination has been suggested as an important factor of poor influenza vaccine effectiveness (VE), though reported conflicting results.MethodsDuring the consecutive A/H3N2-dominant influenza seasons between 2012 and 2015, we comparatively evaluated the VE (repeated vs. current season only) against laboratory-confirmed influenza, pneumonia and hospitalization in the elderly aged ≥65 years with influenza-like illness (ILI). Clinical and demographic data were collected prospectively, and vaccination status of prior and current seasons was verified using the immunization registry data of Korean Centers for Disease Control and Prevention.ResultsDuring the first A/H3N2-dominant season in 2012–2013, influenza vaccine showed statistically significant effectiveness against influenza A infection only and when vaccinated in the current season only (VE 53%, 95% CI 15–77). In the latter two seasons (2013–2015 years), the adjusted VE for influenza A was indistinguishable between repeated vaccination and vaccination in the current season only.ConclusionDuring consecutive influenza A/H3N2 epidemics, poor influenza vaccine effectiveness may be more pronounced among the elderly population with a high annual vaccine uptake rate.     

Comparison of vaccine effectiveness against influenza hospitalization of cell-based and egg-based influenza vaccines, 2017–2018

Egg-based influenza vaccines could be less effective than cell-based vaccine due to adaptive mutations acquired for growth. We conducted a test-negative case-control study at Kaiser Permanente Southern California to assess vaccine effectiveness (VE) against hospitalization for laboratory-confirmed influenza during 2017–2018. Among the 1186 cases and 6946 controls, 74% and 59%, respectively, were ages ≥ 65 years. For any influenza, the adjusted relative VE of cell-based vaccine versus egg-based vaccines was 43% (95% CI: −45% to 77%) for patients ages < 65 years and 6% (95% CI: −46% to 39%) for patients ages ≥ 65 years. For influenza A(H3N2), the adjusted relative VE was 61% (95% CI: −63% to 91%) for patients ages < 65 years and −4% (95% CI: −70% to 37%) for patients ages ≥ 65 years. Statistically significant protection against influenza hospitalization of cell-based vaccine compared to egg-based vaccines was not observed, but further studies in additional influenza seasons are warranted.     

The effectiveness of influenza vaccination among nursery school children in China during the 2016/17 influenza season

BackgroundThe effectiveness of influenza vaccine among nursery school children has not been systematically studied. We conducted a cohort study of children from 13 nursery schools in Suzhou, China, to estimate the effectiveness of influenza vaccine against laboratory-confirmed influenza during 2016–17.MethodsChildren aged 36–72 months were chosen from 13 nursery schools from 3 District in Suzhou. The surveillance started 2 weeks after vaccination during October 2016–February 2017. Class teachers reported the names of students with ILI (influenza-like illness) to study clinicians on each school day. Further, local physicians collected the student’s nasopharyngeal swab or throat swab, either at a study clinic or at the child’s home. The swabs were sent to the National Influenza Network Laboratory in Suzhou Center for Disease Control and Prevention for influenza testing by RT-PCR.ResultA total of 4614 children were enrolled, of which 15 children (vaccinated: 2; unvaccinated: 13) were lost to follow-up. Of the remaining 4599 children, 558 swabs were collected. Among these swabs, 70 samples tested positive for influenza virus; 17 in the vaccinated group (B Victoria: 2; H3N2: 15) and 53 in the unvaccinated group (B Victoria: 14; A(H1N1)pdm09: 1; H3N2: 38). The overall influenza vaccine effectiveness (VE) during the influenza season of 2016–2017 was 20.6%. The incidence of developing ILI symptoms and healthcare seeking behavior through clinical visits was significantly lower in vaccinated children than in the unvaccinated group.ConclusionInfluenza vaccine protection in vaccinated and unvaccinated children showed no statistical difference and the VE percentage varied for different virus subtypes. However, the incidence rate of developing ILI and healthcare seeking behavior was significant lower in the vaccinated group than in the unvaccinated children. Larger studies are required to estimate the VE according to the influenza type, subtype, and lineage during influenza seasons in China in the future.     

Influenza vaccine effectiveness against influenza-associated hospitalization in children: A systematic review and meta-analysis

Vaccination remains the most effective way to prevent influenza infection, albeit vaccine effectiveness (VE) varies by year. Compared to other age groups, children and elderly adults have the highest risk of developing influenza-related complications and requiring hospitalization. During the last years, “test negative design” (TND) studies have been implemented in order to estimate influenza VE. The aim of this systematic review and meta-analysis was to summarize the findings of TND studies reporting influenza VE against laboratory-confirmed influenza-related hospitalization in children aged 6 months to 17 years. We searched the PubMed and Embase databases and identified 2615 non-duplicate studies that required detailed review. Among them, 28 met our inclusion criteria and we performed a random-effects meta-analysis using adjusted VE estimates. In our primary analysis, influenza vaccine offered significant protection against any type influenza-related hospitalization (57.48%; 95% CI 49.46–65.49). When we examined influenza VE per type and strain, VE was higher against H1N1 (74.07%; 95% CI: 54.85–93.30) and influenza B (50.87%; 95% CI: 41.75–59.98), and moderate against H3N2 (40.77%; 95% CI: 25.65–55.89). Notably, influenza vaccination offered higher protection in children who were fully vaccinated (61.79%; 95% CI: 54.45–69.13), compared to those who were partially vaccinated (33.91%; 95% CI: 21.12 – 46.69). Also, influenza VE was high in children less than 5 years old (61.71%; 95% CI: 49.29–74.12) as well as in children 6–17 years old (54.37%; 95% CI: 35.14–73.60). In conclusion, in the pediatric population, influenza vaccination offered significant protection against influenza-related hospitalization and complete annual vaccination should be encouraged.     

Assessment of the effectiveness of the 2003-04 influenza vaccine among children and adults--Colorado, 2003

The 2003-04 influenza season was characterized by the early onset of influenza activity, reports of severe illness, particularly in children, and predominant circulation of an influenza A (H3N2) virus strain that was antigenically different from the influenza A (H3N2) vaccine strain. In 2003, a retrospective cohort study among children and a case-control study among adults in Colorado were conducted to provide preliminary data on the effectiveness of the 2003-04 influenza vaccine. This report summarizes the results of those studies, which indicated vaccine effectiveness (VE) among both adults and children, differing from results of a previous study that did not indicate effectiveness among adults.     

The impact of new universal child influenza programs in Australia: Vaccine coverage,effectiveness and disease epidemiology in hospitalised children in 2018

BackgroundNew jurisdictionally-based vaccination programs were established providing free quadrivalent influenza vaccine (QIV) for preschool Australian children in 2018. This was in addition to the National Immunisation Program (NIP) funded QIV for Indigenous children and children with comorbid medical conditions. We assessed the impact of this policy change on influenza disease burden and vaccine coverage, as well as report on 2018 vaccine effectiveness in a hospital-based surveillance system.MethodsSubjects were recruited prospectively from twelve PAEDS-FluCAN sentinel hospital sites (April until October 2018). Children aged ≤16 years hospitalised with an acute respiratory illness (ARI) and laboratory-confirmed influenza were considered cases. Hospitalised children with ARI who tested negative for influenza were considered controls. VE estimates were calculated from the adjusted odds ratio of vaccination in cases and controls.ResultsA total of 458 children were hospitalised with influenza: 31.7% were <2 years, 5.0% were Indigenous, and 40.6% had medical comorbidities predisposing to severe influenza. Influenza A was detected in 90.6% of children (A/H1N1: 38.0%; A/H3N2: 3.1%; A/unsubtyped 48.6%). The median length of stay was 2 days (IQR: 1,3) and 8.1% were admitted to ICU. Oseltamivir use was infrequent (16.6%). Two in-hospital deaths occurred (0.45%). 12.0% of influenza cases were vaccinated compared with 36.0% of test-negative controls. Vaccine effectiveness of QIV for preventing influenza hospitalisation was estimated at 78.8% (95%CI: 66.9; 86.4).ConclusionsCompared with 2017 (n = 1268 cases), a significant reduction in severe influenza was observed in Australian children, possibly contributed to by improved vaccine coverage and high vaccine effectiveness. Despite introduction of jurisdictionally-funded preschool programs and NIP-funded vaccine for children with risk factors for severe disease, improved coverage is required to ensure adequate protection against paediatric influenza morbidity and mortality.     

Estimating influenza vaccine efficacy from challenge and community-based study data

In this paper, the authors provide estimates of 4 measures of vaccine efficacy for live, attenuated and inactivated influenza vaccine based on secondary analysis of 5 experimental influenza challenge studies in seronegative adults and community-based vaccine trials. The 4 vaccine efficacy measures are for susceptibility (VE(S)), symptomatic illness given infection (VE(P)), infection and illness (VE(SP)), and infectiousness (VE(I)). The authors also propose a combined (VE(C)) measure of the reduction in transmission in the entire population based on all of the above efficacy measures. Live influenza vaccine and inactivated vaccine provided similar protection against laboratory-confirmed infection (for live vaccine: VE(S) = 41%, 95% confidence interval (CI): 15, 66; for inactivated vaccine: VE(S) = 43%, 95% CI: 8, 79). Live vaccine had a higher efficacy for illness given infection (VE(P) = 67%, 95% CI: 24, 100) than inactivated vaccine (VE(P) = 29%, 95% CI: -19, 76), although the difference was not statistically significant. VE(SP) for the live vaccine was higher than for the inactivated vaccine. VE(I) estimates were particularly low for these influenza vaccines. VE(SP) and VE(C) can remain high for both vaccines, even when VE(I) is relatively low, as long as the other 2 measures of vaccine efficacy are relatively high.