Tick-borne Encephalitis Vaccination Research Articles

Tick-Borne Encephalitis Specific Lymphocyte Response after Allogeneic Hematopoietic Stem Cell Transplantation Predicts Humoral Immunity after Vaccination.

The aim of this prospective study was to assess lymphocyte proliferative and cytokine response prior to and following tick-borne encephalitis (TBE) immunization among patients after allogeneic hematopoietic stem cell transplantation (HSCT). Seventeen adult patients 11–13 months after HSCT and eight unvaccinated healthy adults received up to three TBE vaccinations. Following in vitro stimulation with TBE-antigen, lymphocyte proliferation and cytokine secretion (IL-2, IL-10, IL-13, TNF-alpha, IFN-gamma, GM-CSF) were analyzed by thymidine incorporation assay and the Luminex system. Ten patients (59%) showed significant baseline TBE-specific lymphocyte proliferation (stimulation index (SI) > 3) prior to vaccination, but none of the unvaccinated controls (p = 0.002). All patients with a TBE-specific antibody response after two vaccinations (at least 2-fold increase of neutralization test titers) exhibited a strong TBE-specific lymphocyte proliferative response at baseline (SI > 10). Patients with sibling donors had a significantly stronger baseline TBE-specific lymphocyte proliferative and IL-13 cytokine response than patients with unrelated donors (p < 0.05). In conclusion, a relevant proportion of patients showed TBE-specific lymphocyte proliferative and cytokine responses prior to vaccination after HSCT, which predicted the humoral response to the vaccine. Patients with vaccinated sibling donors were more likely to elicit a cellular immune response than patients with unrelated donors of unknown vaccination status.

Knowledge and vaccination practices among family physicians in northeastern France regarding tick-borne encephalitis virus

Tick-borne encephalitis (TBE) cases have been emerging in Europe. The Franche-Comte area, in northeastern France, borders Switzerland, but the two countries differ in their approach to TBE surveillance and prevention. Because family physicians (FPs) are in direct contact with the local population, at-risk of infected tick bites, they need to be well aware of TBE epidemiology and management. An observational survey was performed in 2019 in order to investigate Franche-Comte physicians’ knowledge and vaccination practices with regard to TBE. Standardized online questionnaires were sent to a list of FPs practicing in Franche-Comte. The questionnaires included socio-demographic details, questions about TBE knowledge, symptomatology and vaccination. The response rate was 14.7%. FPs practicing in rural areas reported a significantly higher frequency of consultations for tick bites. While 81% of FPs indicated that they had some knowledge about TBE, only 20% were at ease with its clinical symptomatology. Thirty-one % of the FP participants performed TBE vaccinations. A general lack of knowledge about TBE and its clinical symptoms was observed in this survey. FPs play an essential role in screening and preventing TBE, especially those practicing in rural areas and in areas bordering Switzerland.

In Vitro Characterization of the Innate Immune Pathways Engaged by Live and Inactivated Tick-Borne Encephalitis Virus.

Tick-borne encephalitis virus (TBEV) infection can lead to inflammation of the central nervous system. The disease can be effectively prevented by whole inactivated virus vaccines. Here, we investigated the innate immune profile induced in vitro by the antigen component of the vaccines, inactivated TBEV (I-TBEV), to gain insights into the mechanism of action of the TBE vaccine as compared to the live virus. To this end, we exposed human peripheral blood mononuclear cells (PBMCs) to inactivated and live TBEV and assessed cellular responses by RNA sequencing. Both inactivated and live TBEV significantly induced an interferon-dominated gene signature and an increased RIG-I-like receptor (RLR) expression. Using pathway-specific inhibitors, we assessed the involvement of pattern recognition receptors in the sensing of inactivated or live TBEV. Only RLR pathway inhibition significantly suppressed the downstream cascade induced by I-TBEV, while responses to the replicating virus were impacted by the inhibition of RIG-I-like, as well as Toll-like, receptors. Our results show that inactivated and live TBEV predominantly engaged an interferon response in our in vitro PBMC platform, and indicate RLRs as the main pattern recognition receptors involved in I-TBEV sensing.

Experimental Assessment of Possible Factors Associated with Tick-Borne Encephalitis Vaccine Failure.

Currently the only effective measure against tick-borne encephalitis (TBE) is vaccination. Despite the high efficacy of approved vaccines against TBE, rare cases of vaccine failures are well documented. Both host- and virus-related factors can account for such failures. In this work, we studied the influence of mouse strain and sex and the effects of cyclophosphamide-induced immunosuppression on the efficacy of an inactivated TBE vaccine. We also investigated how an increased proportion of non-infectious particles in the challenge TBE virus would affect the protectivity of the vaccine. The vaccine efficacy was assessed by mortality, morbidity, levels of viral RNA in the brain of surviving mice, and neutralizing antibody (NAb) titers against the vaccine strain and the challenge virus. Two-dose vaccination protected most animals against TBE symptoms and death, and protectivity depended on strain and sex of mice. Immunosuppression decreased the vaccine efficacy in a dose-dependent manner and changed the vaccine-induced NAb spectrum. The vaccination protected mice against TBE virus neuroinvasion and persistence. However, viral RNA was detected in the brain of some asymptomatic animals at 21 and 42 dpi. Challenge with TBE virus enriched with non-infectious particles led to lower NAb titers in vaccinated mice after the challenge but did not affect the protective efficacy.

Dynamics and Extent of Non-Structural Protein 1-Antibody Responses in Tick-Borne Encephalitis Vaccination Breakthroughs and Unvaccinated Patients.

Tick-borne encephalitis (TBE) has a substantial impact on human public health in many parts of Europe and Asia. Effective inactivated purified whole-virus vaccines are in widespread use in TBE-endemic countries. Nevertheless, vaccination breakthroughs (VBTs) with manifest clinical disease do occur, and their specific serodiagnosis was shown to be facilitated by the detection of antibodies to a non-structural protein (NS1) that is produced during virus replication. However, recent data have shown that NS1 is also present in the current inactivated vaccines, with the potential of inducing corresponding antibodies and obscuring a proper interpretation of NS1-antibody assays for diagnosing VBTs. In our study, we quantified anti-virion and anti-NS1 antibody responses after vaccination as well as after natural infection in TBE patients, both without and with a history of previous TBE vaccination (VBTs). We did not find significant levels of NS1-specific antibodies in serum samples from 48 vaccinees with a completed vaccination schedule. In contrast, all TBE patients mounted an anti-NS1 antibody response, irrespective of whether they were vaccinated or not. Neither the dynamics nor the extent of NS1-antibody formation differed significantly between the two cohorts, arguing against substantial NS1-specific priming and an anamnestic NS1-antibody response in VBTs.

Chapter 14: Prevention: vaccines and immunoglobulins

Worldwide there are 6 different TBE vaccines – two from Western Europe, three from Russia and one from China. The two western European vaccines and one of the Russian vaccines have an adult and a pediatric formulation. The products names are FSME IMMUN and FSME-IMMUN Junior; Encepur adults and Encepur children, Klesch-E-Vac, EnceVir and EnceVir Neo, Dry lyophilized TBE Moscow and Sen Tai Bao. All TBE vaccines except the one from China have similar but not identical immunization schedules with primary immunization (&gt;3 doses) and regular booster vaccinations. For FSME-IMMUN, Encepur and EnceVir rapid immunization schedules are also licensed. The Chinese vaccine is given with 2 primary doses 2 weeks apart followed by annual boosters. All vaccines induce significant immune responses. In the absence of a formal correlate of protection, the presence of neutralizing antibodies is used as a surrogate marker for protection. Recent clinical studies show long-term seropersistence of TBE antibodies after the first booster vaccination (dose 4) with the two European vaccines. An effectiveness of approximately 99% (years 2000–2006) and 98.7% (years 2000-2011) was calculated for regularly vaccinated persons in Austria, a country with established high vaccination uptake. Whereas in Western Europe post-exposure prophylaxis with immunoglobulins was discontinued in the late 1990s, in the highly endemic regions of Russia it continues to be common practice. Both – FSME-IMMUN and Encepur are well tolerated with a well-established safety profile. TBE-Moscow and EnceVir appear to be somewhat more reactogenic.

Chapter 6: TBE in children

Most cases of TBE in childhood will present similarly as in adults. However, a more diffuse clinical picture is seen especially in preschool children. Laboratory evaluation may show elevated blood inflammatory indices, but cerebrospinal fluid analysis and anti-TBEV serology are needed for establishing the diagnosis. There is no specific treatment for TBE; supportive care needs to be provided based on the individual clinical course. The mortality in pediatric TBE is very low, but severe courses have been reported in a fraction of the children. Long-term somatic residua exist, but are uncommon (2%) in childhood TBE. Yet, long-term symptoms and neurodevelopmental/cognitive deficits are seen in 10–40% of infected children. Protective immunity can be elicited in children by TBE vaccines as of 1 year of age.

Tick-Borne Encephalitis Vaccination Protects from Alimentary TBE Infection: Results from an Alimentary Outbreak.

In May 2017, a hospitalized index case of tick-borne encephalitis (TBE) was confirmed by Serology. The case was linked to alimentary infection by raw milk from a goat farm in the region of Tübingen, Baden-Württemberg, Germany, where no previous TBE cases in the area had been reported before. The TBE focus was confirmed by isolation of the TBE virus from ticks and Serological confirmation of past infection in one of the five flock goats. Additional investigations by the local public health office identified 27 consumers of goat milk at the putative period of exposure. For 20/27 exposed persons, anamnestic information was gained by the local public health office. Twelve/fourteen exposed and non-vaccinated people developed clinical illness and were confirmed as TBE cases by Serology. Five/six vaccinated and exposed people did not develop the disease. The one exposed and vaccinated person had their last TBE vaccination booster more than 15 years ago, and therefore a booster was more than 10 years overdue. None of the regularly vaccinated and exposed persons developed clinical overt TBE infection. We report the first known TBE outbreak, during which, protection by TBE vaccination against alimentary TBE infection was demonstrated.

Comparison of Clinical, Laboratory and Immune Characteristics of the Monophasic and Biphasic Course of Tick-Borne Encephalitis.

The biphasic course of tick-borne encephalitis (TBE) is well described, but information on the monophasic course is limited. We assessed and compared the clinical presentation, laboratory findings, and immune responses in 705 adult TBE patients: 283 with monophasic and 422 with biphasic course. Patients with the monophasic course were significantly (p ≤ 0.002) older (57 vs. 50 years), more often vaccinated against TBE (7.4% vs. 0.9%), more often had comorbidities (52% vs. 37%), and were more often treated in the intensive care unit (12.4% vs. 5.2%). Multivariate logistic regression found strong association between the monophasic TBE course and previous TBE vaccination (OR = 18.45), presence of underlying illness (OR = 1.85), duration of neurologic involvement before cerebrospinal fluid (CSF) examination (OR = 1.39), and patients’ age (OR = 1.02). Furthermore, patients with monophasic TBE had higher CSF levels of immune mediators associated with innate and adaptive (Th1 and B-cell) immune responses, and they had more pronounced disruption of the blood–brain barrier. However, the long-term outcome 2–7 years after TBE was comparable. In summary, the monophasic course is a frequent and distinct presentation of TBE that is associated with more difficult disease course and higher levels of inflammatory mediators in CSF than the biphasic course; however, the long-term outcome is similar.

Rubella and tick-borne encephalitis vaccination rates among staff and students at Austrian University of Applied Sciences.

Rubella and tick-borne encephalitis (TBE) are infectious diseases caused by viruses. Rubella is an air-borne infection. TBE, on the other hand, is transmitted by virus-infected ticks. Both diseases show specific symptoms after an incubation period of approximately 10 days. The Austrian vaccination plan recommends vaccinations against both viruses, as only these can protect against both infectious diseases. Because of both, an increase in measles infections and the high endemic rate of TBE in Austria, our goal was to evaluate the vaccination rate, antibody titre and general level of knowledge with respect to these two infections amongst adults in order to identify possible nescience regarding booster vaccination and general titre rates. One hundred ninety-nine people participated in the study of the TBE and rubella titre determination. We used indirect ELISA and asked the volunteers to complete a questionnaire. The analysis of the results showed a vaccination coverage rate of over 90% for both diseases. Our findings lead to the conclusion that the protection through immunization is very high and the vaccines used are extremely effective, particularly as some individuals do not adhere to the recommended vaccination schedule.

Expert consensus on informed consent for vaccination (part two)

The Vaccine Administration Law of the People's Republic of China and other relevant laws require that vaccine recipients or their guardians be educated about vaccines and how they work, and described in general the methods and contents of such vaccination education. With the new law and "Standard Operational Procedures for Immunization" as foundation documents, and in consultation with experts at home and abroad, the Chinese Preventive Medicine Association developed a consensus statement about informed consent for vaccination. This consensus statement is written for disease control and prevention health care personnel in vaccination services and describes the educational content of informed consent, a theoretical framework for immunization and immunization knowledge, the informed consent processes, principles of planning for vaccination, and an informed consent form. Part two of the consensus includes influenza vaccine, pneumococcal vaccine, haemophilus influenzae type b containing vaccine, enterovirus type 71 inactivated vaccine, rotavirus vaccine, varicella attenuated live vaccine, herpes-zoster vaccine, human papillomavirus vaccine, rabies vaccine, hemorrhagic fever with renal syndrome vaccine, leptospira vaccine, anthrax vaccine, hepatitis E vaccine, cholera vaccine, typhoid vaccine, tick-borne encephalitis vaccine.

Expert consensus on informed consent for vaccination (part two)

The Vaccine Administration Law of the People's Republic of China and other relevant laws require that vaccine recipients or their guardians be educated about vaccines and how they work, and described in general the methods and contents of such vaccination education. With the new law and "Standard Operational Procedures for Immunization" as foundation documents, and in consultation with experts at home and abroad, the Chinese Preventive Medicine Association developed a consensus statement about informed consent for vaccination. This consensus statement is written for disease control and prevention health care personnel in vaccination services and describes the educational content of informed consent, a theoretical framework for immunization and immunization knowledge, the informed consent processes, principles of planning for vaccination, and an informed consent form. Part Two of the consensus includes influenza vaccine, pneumococcal vaccine, haemophilus influenzae type b containing vaccine, enterovirus type 71 inactivated vaccine, rotavirus vaccine, varicella attenuated live vaccine, herpes-zoster vaccine, human papillomavirus vaccine, rabies vaccine, hemorrhagic fever with renal syndrome vaccine, leptospira vaccine, anthrax vaccine, hepatitis E vaccine, cholera vaccine, typhoid vaccine, and tick-borne encephalitis vaccine.

Immunity to TBEV Related Flaviviruses with Reduced Pathogenicity Protects Mice from Disease but Not from TBEV Entry into the CNS.

Tick-borne encephalitis virus (TBEV) is a leading cause of vector-borne viral encephalitis with expanding endemic regions across Europe. In this study we tested in mice the efficacy of preinfection with a closely related low-virulent flavivirus, Langat virus (LGTV strain TP21), or a naturally avirulent TBEV strain (TBEV-280) in providing protection against lethal infection with the highly virulent TBEV strain (referred to as TBEV-Hypr). We show that prior infection with TP21 or TBEV-280 is efficient in protecting mice from lethal TBEV-Hypr challenge. Histopathological analysis of brains from nonimmunized mice revealed neuronal TBEV infection and necrosis. Neuroinflammation, gliosis, and neuronal necrosis was however also observed in some of the TP21 and TBEV-280 preinfected mice although at reduced frequency as compared to the nonimmunized TBEV-Hypr infected mice. qPCR detected the presence of viral RNA in the CNS of both TP21 and TBEV-280 immunized mice after TBEV-Hypr challenge, but significantly reduced compared to mock-immunized mice. Our results indicate that although TBEV-Hypr infection is effectively controlled in the periphery upon immunization with low-virulent LGTV or naturally avirulent TBEV 280, it may still enter the CNS of these animals. These findings contribute to our understanding of causes for vaccine failure in individuals vaccinated with TBE vaccines.

Epidemiology, diagnosis, and prevention of tick-borne encephalitis in Poland and selected European countries - a position statement of the Polish group of experts

Tick-borne encephalitis (TBE) is one of the most common viral neuroinfections in Poland. Detection of specific IgM and IgG anti- TBE antibodies in the serum or cerebrospinal fluid with enzyme-linked immunosorbent assay (ELISA) is a method of choice in TBE diagnostics. No effective antiviral treatment is available for TBE. Increased intracranial pressure, epileptic seizures, and other neurological symptoms in the course of TBE are managed with standard procedures. A routine use of corticosteroids is not recommended. Adults with TBE-related neurological sequelae should undergo physical mobilization and periodic neurological assessments. All patients ought to control their psychological condition and visit a physician in case of worrisome symptoms. Additionally, children need to undergo regular psychological and otolaryngologic consultations. Notably, TBE cases are reported across Poland; therefore, the entire country must be considered as a TBE risk region. The degree of endemicity can be variable in particular parts of the country. Immunization against TBE containing a European subtype of the virus is the most effective prophylactic method. In areas where the disease is highly endemic (according to the WHO definition of ≥5 cases/100 000 population/year), immunization needs to be offered to all ages. Vaccination is recommended in the communities living in areas of moderate TBE endemicity (1-5 cases/100 000/ year), in particular for individuals at high risk of a TBE infection as well as children and the elderly. Vaccination should also be offered to subjects living in areas where TBE occurrence is rare (<1 case/100 000/year) but who are at high risk of infection. A TBE vaccine is recommended to the following populations at high risk of TBE: a) individuals undertaking outdoor leisure activities, b) all professionals working outdoors, particularly in green areas, and c) individuals traveling to endemic areas, if activities during their visit may pose a risk of a tick bite. Post-exposure immunization is not recommended. Med Pr. 2021;72(2):193-210.

Vaccination against tick-borne encephalitis (TBE) after autologous and allogeneic stem cell transplantation

IntroductionOur aim was to assess response and side effects of 4 doses of TBE vaccine to patients (pts) after allo- and autologous stem cell transplantation (SCT). PATIENTS: Included were 104 pts with leukaemia, myeloma and lymphoma, median age 61 yrs. METHODS: Vaccine (FSME-Immun®) was given at 9, 10, 12, and 21 months post-transplant. Serum samples were obtained before and after vaccinations. Healthy controls (n = 27) received 3 vaccinations. Assessments of TBE specific IgG antibodies were performed by Enzygnost anti-TBE ELISA test (Siemens, Sweden). ResultsAntibody levels (>12 U/mL; “seropositivity”) were seen in 77% and 80% of pts after allo- and autoSCT; IgG levels; 89 vs 94 U/mL. Ongoing chronic GvHD and immunosuppression (n = 29) was associated with sero-negativity in the last sample (p = 0.007). All controls (n = 27) developed protective antibody levels. ConclusionsTBE vaccination was safe, and 4 doses starting 9 months post-SCT, induced seropositivity in a vast majority of pts.

Innate and adaptive immunity during infection and immunization with inactivated tick-borne encephalitis vaccine

Innate and adaptive immunity during infection and immunization with inactivated tick-borne encephalitis vaccine

Vaccination rate and adherence of tick-borne encephalitis vaccination in Germany

BackgroundTick-borne encephalitis (TBE) is an arboviral infection of the central nervous system. As there is no causal treatment of TBE, disease prevention by vaccination is especially important. Immunization consists of a three-dose primary vaccination schedule, followed by regular booster doses. In Germany, the Standing Committee on Vaccination (STIKO) at the Robert Koch-Institute recommends TBE vaccination for all those at high risk of contracting TBE. This includes individuals living in, traveling to and/or working in risk areas, and being exposed to ticks. To our knowledge, there are currently no reliable data on TBE vaccination rates in Germany available. MethodsThis retrospective cohort study based on anonymized German health claims data was conducted to determine vaccination rates of TBE primary immunization in 2012 to 2015 by federal state, compliance with the vaccination schedule, and TBE vaccination uptake for the 2011 birth cohort. Vaccination protection rates for each federal state were simulated based on a compartmental model. ResultsVaccination rates of an initiated primary immunization ranged from about 3% in the southern federal states to <1% in the northern federal states. Across all federal states, compliance with the vaccination schedule decreased with each subsequent vaccination. Slightly higher TBE vaccination uptake was determined in the 2011 birth cohort, as compared to the German school entry health examination statistics in 2017. Simulated vaccination protection rates for each federal state ranged from 10% in Hamburg to 51% in Baden-Wuerttemberg. ConclusionsWhile there was an overall low vaccination uptake and a discrepancy between areas of high vs. low TBE risk, this study also indicates a concerning decline in vaccination compliance. Vaccinating physicians should address the importance of adherence upon initiation of TBE vaccination.

Human Diploid Fibroblast Cell Lines - a Model System for Studying Immunodulatory Properties of Modern Immunobiological Drugs and Viruses.

The immunomodulatory properties of immunobiological drugs Glutoxim and Phosprenyl we well as vesicular stomatitis virus and inactivated tick-borne encephalitis vaccine virus were studied using human diploid fibroblast cell line from the collection of M. P. Chumakov Federal Research Center for Research and Development of Immunobiological Products. All tested preparations exhibited immunomodulatory activity in human diploid fibroblast cell line. Glutoxim in doses of 0.1 and 0.25 μg/ml stimulated production of IL-6 and IL-10 during 24-48 h of culturing, but did not stimulate production of IL-1β. Phosprenyl, on the contrary, increased production of IL-1β and the levels of IL-6 and IL-10. Vesicular stomatitis virus stimulated the production of IL-1β, IL-6, and IL-10, while inactivated tick-borne encephalitis vaccine virus stimulated the production of cytokines IL-8 and IL-18. Immunomodulatory activity of inactivated tick-borne encephalitis vaccine virus was first demonstrated in the in vitro system.

Analysis of Tick-borne Encephalitis vaccination coverage and compliance in adults in Switzerland, 2018

BackgroundOverall incidence and geographic range of Tick-borne Encephalitis (TBE), a vaccine preventable infection, have steadily increased in Switzerland over the last 50 years. While fully subsidized vaccination has been recommended in many areas for well over a decade, vaccine coverage and variables associated with vaccination compliance among Swiss adults are poorly understood. MethodsIn 2018 we conducted a national, cross-sectional survey of vaccination cards evaluating TBE vaccination coverage and compliance among adults (18-79) in Switzerland. ResultsNationwide TBE vaccination coverage was 41.7% (range 14.3% to 60.3%) for 1 dose and 32.9% (range 8.4% to 50.4%) for a complete primary series (3 doses). There was a significant correlation between average disease incidence by canton (2009-2018) and vaccine coverage at both 1 and 3 doses. Of the overall population, 9.5% had received at least one TBE booster vaccination with large regional coverage variation. We estimated that 23% of adults in Switzerland would be protected from infection based on their vaccination history and 135 (95% CI: 112-162) TBE cases were prevented in 2018. Individuals reporting previous experience with tick-associated health problems, those frequently in nature or those with “high” perceived risk of contracting TBE, were significantly more likely to have received at least one vaccine dose, indicating a positive impact of awareness on vaccination compliance. We also calculated a TBE incidence rate of 6.83/100,000 among the unvaccinated adult population in Switzerland and estimated vaccine effectiveness at 91.5% (95% CI: 90.9-92.0%). ConclusionsThese findings provide an important reference for TBE vaccination levels in Switzerland and further suggest that public health interventions promoting knowledge of TBE health impacts and risk factors may be beneficial in improving TBE vaccination coverage but should be tailored to account for heterogeneity in vaccine uptake.

Effectiveness of Specific Prevention of Tick-Borne Encephalitis

Vaccination remains the only way to prevent tick-borne encephalitis (TBE). All TBE vaccines are based on strains of the Far Eastern and European subtypes of TBE virus. Currently, the Siberian subtype of the virus, which differs from the vaccine strains, accounts for 80–100% of the genetic population of TBE virus in most of Russia. The proportion of TBE vaccinated patients among those infected was different from year to year in Russia, e.g. 3.9% in 2012 and 1.5% in 2018, there were also some fatal cases registered among vaccinated patients. In this regard, evaluation of the effectiveness of vaccination against various genetic subtypes of TBE is a promising area of research. The purpose of this study was to summarise the results of studies investigating effectiveness of specific prevention of TBE as regards various genetic subtypes of the virus. The paper analyses data on the effectiveness of TBE vaccination in experimental settings and in real life. It was demonstrated that the use of vaccines for prevention of TBE is effective, provided the vaccination coverage is not less than 80%. The paper cites the data from a long-term study of the stability and protective activity of vaccine immunity against TBE virus strains isolated in highly endemic territories. It was established that TBE vaccines have high immunogenic activity and contribute to the production of stable protective antibodies against the strains of the three genetic subtypes of the virus. Protective efficacy of vaccination depends on the number of vaccinations received, the vaccination scheme, gender and age of those vaccinated. The paper concludes by saying that further studies are needed to assess TBE vaccine efficacy in order to improve vaccination tactics, to better understand causes of morbidity and mortality among vaccinated individuals.