+
MODEL
Travel Medicine and Infectious Disease (2014) xx, 1e23
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevierhealth.com/journals/tmid
REVIEW
Childhood vaccination associated adverse events by sex: A literature review ¨hli Weber a,*, Patricia Schlagenhauf b,1 Sandra Ko a
School of Public Health at the Universities of Basel, Bern and Zu¨rich, Hirschengraben 84, 8001 Zu¨rich, Switzerland b Division of Epidemiology and Communicable Diseases, University of Zu¨rich Centre for Travel Medicine, WHO Collaborating Centre for Travellers’ Health, Hirschengraben 84, 8001 Zu¨rich, Switzerland Received 26 August 2013; received in revised form 23 January 2014; accepted 28 January 2014
KEYWORDS Adverse events; Measlesemumps erubella vaccine (MMR); Hepatitis B vaccine (HBV); Human papilloma virus vaccine (HPV); Childhood; Sex
Summary Background: Most approved medicines, including vaccines can be associated with adverse events. A vaccine adverse event is defined as any untoward medical occurrence which follows vaccination, but which does not necessarily have a causal relationship with the administration of the vaccine. Methods: The objective of this structured literature review is to analyse the adverse events reported with vaccinations usually done during childhood and adolescence: human papilloma virus vaccine, hepatitis B vaccine and measlesemumpserubella vaccine. We evaluated the vaccine literature on children and adolescents by sex. We searched the Cochrane Database, Medline (Pubmed) and Embase using predefined terms. Results: Of the 417 publications retrieved from searches in the 3 databases, 89 papers (21%) were identified as potentially relevant to the review. On further scrutiny 41 of these satisfied the criteria for inclusion in the analysis. Serious adverse events related to vaccinations were rare. We found some possible sex related vaccine adverse events. Few trials however reported adverse events by age and sex and very few analyses evaluated the observed differences. Conclusions: Despite earlier calls for sex-specific analyses of clinical studies, we found that vaccine trials were rarely reported and published by sex. Prospectively collated vaccine safety data in children and adolescents should be analysed by age and sex, so that clinical trial results can form an evidence base for vaccine practice recommendations. ª 2014 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: þ41 44 634 46 30. E-mail addresses: [email protected] (S.Ko ¨hli-Weber), [email protected] (P. Schlagenhauf). 1
Tel.: þ41 44 634 46 30.
http://dx.doi.org/10.1016/j.tmaid.2014.01.008 1477-8939/ª 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Weber SK, Schlagenhauf P, Childhood vaccination associated adverse events by sex: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.01.008
+
MODEL
2
S.K. Weber, P. Schlagenhauf
Introduction Vaccinations are one of the most important and effective preventive medical measures [1,2]. The goal of vaccination is to prevent disease. The impact of vaccination is not only limited to the single individual, but also has a positive impact on society. The pre-travel consult often offers a possibility to check and if necessary complete childhood vaccination schedules. Depending of the type of vaccine, immunization can be administered to persons of any age group, including infants, children and adolescents. Most of the therapeutically approved products, including vaccinations, may be associated with adverse events, most of them being mild, but in rare cases fatal adverse events occur. The latter very often influences the attitude towards immunization in our society and tends to result in resistance and refusal of its use in developed countries [3e5]. This behaviour can be observed after the successful disappearance of infectious diseases, when the benefit of further vaccination is no longer obvious [6]. This development is a major challenge in public health, as vaccine-preventable infectious diseases are re-emerging (e.g. measles in Switzerland [7]). An adverse event following immunization (AEFI) is defined as any untoward medical occurrence which follows immunization but which does not necessarily have a causal relationship with the usage of the vaccine [8]. An adverse event can be local or systemic; this includes symptoms like injection site reactions (e.g. pain, swelling), fever, fatigue, headache and joint pain. In rare cases, the adverse event can be serious such as an anaphylactic shock or death. Live vaccines can in rare cases lead to the manifestation of the disease (e.g. oral polio vaccine: vaccine induced polio or yellow fever: vaccine induced viscerotropic disease). Besides the active vaccine agent, other vaccine additives also can be responsible for the adverse event(s) [9], [Table 1]. The pharmacovigilance [10,11] is a very important component of immunization programs in order to guarantee the safety of new vaccines and to react quickly and
Table 1
Adverse reactiona
Immunizationb Serious adverse event or reactiona Side effecta Unexpected adverse reactiona Vaccineb a
Does the literature describe any sex-differences in the adverse event profile following human papilloma virus vaccine, MMR vaccine and hepatitis B vaccine vaccination? If yes, what are the differences? To what extent can they be attributed to specific causes, in order that recommendations can be derived?
Definitions of Terms (WHO and CDC).
Adverse eventa
b
adequately to new concerns. Passive surveillance is unable to determine the causal relationship between an adverse event following immunization. If a vaccine safety signal is generated by passive surveillance, further epidemiological studies are required in order to evaluate the likelihood of a causal relationship [12]. A review published in 2009 could already demonstrate that the pathophysiology of the sex-differences in local reactions following immunization was clearly multifactorial, with hypersensitivity reactions, route of administration and hormonal factors being suggested [13]. In another review by the same author [14] in comparative data he concluded, that intramuscular injection was associated with significantly lower rates of injection site reactions and a greater immune response than the subcutaneous route. The objective of this review is to analyse the adverse events reported with human papilloma virus vaccine, measlesemumpserubella vaccine and hepatitis B vaccine in children and adolescents by sex. Furthermore this review will analyse if there is a relationship between the current vaccination practice and the adverse event profile. New data from clinical studies can lead to changes in recommendations for the vaccination practice. For example the time schedule for MMR vaccination 1 and 2 has been modified based on clinical experience. The purpose of this analysis is to collate evidence to highlight and minimize sex specific adverse events following immunization (AEFI) and this evidence may be useful to guide practice in the future. The goals of this review are to address the following questions:
Medical occurrence temporally associated with the use of a medicinal product, but not necessarily causally related. A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or modifications of physiological function. The process by which a person or animal becomes protected against a disease. This term is often used interchangeably with vaccination or inoculation. Any untoward medical occurrence that at any dose results in death, is life threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation or results in persistent of significant disability or incapacity. Unintended effect occurring at normal dose related to the pharmacological properties. Not consistent with applicable product information or characteristics of drug. A product that produces immunity therefore protecting the body from the disease. Vaccines are administered through needle injections, by mouth and by aerosol.
WHO: http://www.who.int/medicines/areas/quality_safety/safety_efficacy/trainingcourses/definitions.pdf. CDC, Definition of terms: http://www.cdc.gov/vaccines/vac-gen/imz-basics.htm.
Please cite this article in press as: Weber SK, Schlagenhauf P, Childhood vaccination associated adverse events by sex: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.01.008
+
MODEL
Childhood vaccination associated adverse events by sex
Methods Literature search sources The Cochrane Database was searched using the terms: MeSH Human Papilloma Virus Vaccine e adverse effects MeSH MeasleseMumpseRubella Vaccine e adverse effects MeSH Hepatitis B Vaccines e adverse effects The Medline (Pubmed) Database was searched using the following terms: ((hpv/mmr/hepatitis b vaccine [MeSH Terms]) AND adverse events) AND (children and adolescents) ((hpv/mmr/hepatitis b vaccine [MeSH Terms]) AND adverse events) AND (girls and boys) The Embase Database was searched using the following terms: ‘human papilloma virus vaccine’/exp OR ‘human papilloma virus vaccine’ AND ‘adverse events’ AND ‘children and adolescents’ ‘human papilloma virus vaccine’/exp OR ‘human papilloma virus vaccine’ AND ‘adverse events’ AND (‘children’/exp OR ‘children’) ‘human papilloma virus vaccine’/exp OR ‘human papilloma virus vaccine’ AND ‘adverse events’ AND ‘adolescents’ ‘mmr vaccine’/exp OR ‘mmr vaccine’ AND ‘adverse events’ AND ‘children and adolescents’ ‘mmr vaccine’/exp OR ‘mmr vaccine’ AND ‘adverse events’ AND ‘children’ ‘mmr vaccine’/exp OR ‘mmr vaccine’ AND ‘adverse events’ AND ‘ adolescents’ ‘hepatitis b vaccines’/exp OR ‘hepatitis b vaccines’ AND ‘adverse events’ AND ‘children and adolescents’ ‘hepatitis b vaccines’/exp OR ‘hepatitis b vaccines’ AND ‘adverse events’ AND ‘children’ ‘hepatitis b vaccines’/exp OR ‘hepatitis b vaccines’ AND ‘adverse events’ AND ‘adolescents’ ‘human papilloma virus vaccine’/exp OR ‘human papilloma virus vaccine’ AND ‘adverse events’ AND ‘girls and boys’ ‘human papilloma virus vaccine’/exp OR ‘human papilloma virus vaccine’ AND ‘adverse events’ AND ‘girls’ ‘human papilloma virus vaccine’/exp OR ‘human papilloma virus vaccine’ AND ‘adverse events’ AND ‘boys’ ‘mmr vaccine’/exp OR ‘mmr vaccine’ AND ‘adverse events’ AND ‘girls and boys’ ‘mmr vaccine’/exp OR ‘mmr vaccine’ AND ‘adverse events’ AND ‘girls’ ‘mmr vaccine’/exp OR ‘mmr vaccine’ AND ‘adverse events’ AND ‘boys’ ‘hepatitis b vaccines’/exp OR ‘hepatitis b vaccines’ AND ‘adverse events’ AND ‘girls and boys’ ‘hepatitis b vaccines’/exp OR ‘hepatitis b vaccines’ AND ‘adverse events’ AND ‘girls’ ‘hepatitis b vaccines’/exp OR ‘hepatitis b vaccines’ AND ‘adverse events’ AND ‘boys’
3 The search was limited to articles published and accessible online up to December 31st 2012. There was no limit set for the beginning of the search. The first author identified articles that were possibly or highly likely to be relevant to the review, on the basis of the title and the abstract. The title and the abstract should contain or indicate information on adverse events following immunization in children and adolescents, if possible of both sexes, referring to the measlesemumpserubella vaccine, hepatitis B vaccine and human papilloma virus vaccine. This list was then reviewed by both authors who also agreed on which articles should be selected.
Extraction of items from the publication and inclusion criteria The following points listed below needed to be fulfilled in the title and abstract (which were supposed to be the minimum requirements), to identify publications for analysis. Reference: article, title, authors Abstract: Indicating relevance to the research objectives Purpose: according to the authors’ criteria for inclusion. These criteria are: Does the literature describe any sexdifferences in the adverse events following human papilloma virus vaccine, measlesemumpserubella vaccine and hepatitis B vaccine? Study designs: Study designs for inclusion in the review, if available: meta-analysis, systematic reviews, randomized clinical trials and other cohort studies. The reference lists of some of the systematic reviews were useful to identify some papers that did not come up in the search. Population: Demographic data (children and adolescents, males and females) Incident: adverse events after human papilloma virus vaccine, measlesemumpserubella vaccine and hepatitis B vaccine, not administered at the same time with other (combined) vaccines such as diphtheriaetetanusepertussis vaccine, diphtheriaetetanusepertussisehaemophilusepolio vaccine and other combined vaccines applied in children and adolescents. Control: Description of the control group or alternative intervention like application of another vaccine like e.g. hepatitis A vaccine or other vaccines. Outcome: Results of the incidence, sex-differences in the adverse event profile in children and adolescents, public health proposals and recommendations.
Results Data analysis Of the 417 publications retrieved from one or more of the three databases [Table 2], 89 (21%) were identified as being potentially relevant to the review, 41 (36.5%) were considered to satisfy the list of criteria for inclusion in this review.
Please cite this article in press as: Weber SK, Schlagenhauf P, Childhood vaccination associated adverse events by sex: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.01.008
+
MODEL
4
S.K. Weber, P. Schlagenhauf Table 2
Source database and number of publications.
Database
Cochrane
Pubmed
Embase
Read Inclusion Quoted Exclusion Read Inclusion Quoted Exclusion Read Inclusion Quoted Exclusion
Human papilloma virus vaccine
Measles mumps rubella vaccine
Hepatitis B vaccine
0 0 0 0 27 12 8 15 7 5 4 2
4 3 0 1 14 7 6 7 14 7 5 7
1 0 0 1 16 5 2 11 6 2 1 4
Read: Publications have been read, selected by information of the title and abstract, being potentially relevant for the review. Inclusion: Publications included for evaluation. Quoted: Discussed in the text. Exclusion: Publications excluded for evaluation because criteria were not met (did not fulfil the reporting of adverse events by age / sex).
Presentation of the results Adverse events following hepatitis B vaccine Of the 23 selected publications from the three databases, 16 were excluded because they did not fulfil the reporting of adverse events by sex. Of the 7 included papers for our evaluation, 2 reported adverse events only by age [15,16], while Niu et al. [17] was the only study to report on adverse events by different age groups and by sex. 4 publications [18e21] did not have sufficient information for further evaluations [Table 3]. The objective of Martins [15] et al. multicentre, doubleblind prospective study of 2754 subjects was to analyse the immunogenicity and safety of two recombinant vaccines (Butang and Engerix) against hepatitis B. In the children’s age group 1e10 years the results for seroprotection and geometric mean titres were maximal. This group showed the strongest immune response decreasing with age. No serious adverse events related to the vaccine were reported. In 13 cases adverse events following the previous dose led to withdrawal from the study, in only 2 cases there was a clear causal relationship to the vaccine (generalized pruritus in one adolescent and generalized urticaria in one adult). No further age- or sex-specific adverse events analyses were done. Fisher et al. [16] analysed NHIS (National Health Interview Survey) datasets to provide post-marketing surveillance data (probability samples) of infrequent adverse reactions to the hepatitis B vaccine. The authors investigated the association of the vaccine with adverse health outcomes in US children less than 6 years of age and addressed the lack of long-term follow-up after vaccination. Controlling the data simultaneously for race, age and gender, the risk of chronic arthritis, incident cases of pharyngitis/nasopharyngitis and incident cases of acute ear infections were for all 3 diagnoses always
higher among children 0e5 years old who received the vaccination than in children without vaccination. Although in the descriptive summary a distribution by gender has been done and the data were controlled by gender, there was no sex-specific analysis of adverse events. By reviewing case series from 1991 to 1994 of the national Vaccine Adverse Event Reporting System (VAERS), Niu et al. [17] evaluated the post marketing safety of recombinant hepatitis B vaccine given to neonates and infants in the U.S. Analysing the events in neonates and children by severity, no difference by gender could be observed. Fever was the most common serious symptom in neonates. Reported deaths were highest for neonates and infants compared to other age groups, while looking at the total number of adverse events and reported deaths, the rates were higher for male infants. Adverse events following measlesemumpserubella vaccine Of the 32 selected publications from the three databases, 15 were excluded because they did not fulfil the reporting of adverse events by age/sex. Of the 17 included papers for our evaluation, 8 authors reported adverse events by age [22e29], 1 by sex [30] and the remaining 2 by age and sex [31,32]. 6 publications [33e38] did not have sufficient information for further evaluations [Table 4]. The Finnish 14 year prospective follow-up study analysed through a passive surveillance system the causality of severe adverse events related to MMR vaccination [22]. 1.8 million individuals (the age at the time of vaccination ranged from 13 months to 23 years, the main target group being children at the age of 14e18 month and 6 years) received the vaccination, among these 173 potentially serious reactions were asserted to have been caused by the MMR vaccine: 77 neurologic ((febrile seizures in 52 vaccinees 49
MODEL
Travel Medicine and Infectious Disease (2014) xx, 1e23
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevierhealth.com/journals/tmid
REVIEW
Childhood vaccination associated adverse events by sex: A literature review ¨hli Weber a,*, Patricia Schlagenhauf b,1 Sandra Ko a
School of Public Health at the Universities of Basel, Bern and Zu¨rich, Hirschengraben 84, 8001 Zu¨rich, Switzerland b Division of Epidemiology and Communicable Diseases, University of Zu¨rich Centre for Travel Medicine, WHO Collaborating Centre for Travellers’ Health, Hirschengraben 84, 8001 Zu¨rich, Switzerland Received 26 August 2013; received in revised form 23 January 2014; accepted 28 January 2014
KEYWORDS Adverse events; Measlesemumps erubella vaccine (MMR); Hepatitis B vaccine (HBV); Human papilloma virus vaccine (HPV); Childhood; Sex
Summary Background: Most approved medicines, including vaccines can be associated with adverse events. A vaccine adverse event is defined as any untoward medical occurrence which follows vaccination, but which does not necessarily have a causal relationship with the administration of the vaccine. Methods: The objective of this structured literature review is to analyse the adverse events reported with vaccinations usually done during childhood and adolescence: human papilloma virus vaccine, hepatitis B vaccine and measlesemumpserubella vaccine. We evaluated the vaccine literature on children and adolescents by sex. We searched the Cochrane Database, Medline (Pubmed) and Embase using predefined terms. Results: Of the 417 publications retrieved from searches in the 3 databases, 89 papers (21%) were identified as potentially relevant to the review. On further scrutiny 41 of these satisfied the criteria for inclusion in the analysis. Serious adverse events related to vaccinations were rare. We found some possible sex related vaccine adverse events. Few trials however reported adverse events by age and sex and very few analyses evaluated the observed differences. Conclusions: Despite earlier calls for sex-specific analyses of clinical studies, we found that vaccine trials were rarely reported and published by sex. Prospectively collated vaccine safety data in children and adolescents should be analysed by age and sex, so that clinical trial results can form an evidence base for vaccine practice recommendations. ª 2014 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: þ41 44 634 46 30. E-mail addresses: [email protected] (S.Ko ¨hli-Weber), [email protected] (P. Schlagenhauf). 1
Tel.: þ41 44 634 46 30.
http://dx.doi.org/10.1016/j.tmaid.2014.01.008 1477-8939/ª 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Weber SK, Schlagenhauf P, Childhood vaccination associated adverse events by sex: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.01.008
+
MODEL
2
S.K. Weber, P. Schlagenhauf
Introduction Vaccinations are one of the most important and effective preventive medical measures [1,2]. The goal of vaccination is to prevent disease. The impact of vaccination is not only limited to the single individual, but also has a positive impact on society. The pre-travel consult often offers a possibility to check and if necessary complete childhood vaccination schedules. Depending of the type of vaccine, immunization can be administered to persons of any age group, including infants, children and adolescents. Most of the therapeutically approved products, including vaccinations, may be associated with adverse events, most of them being mild, but in rare cases fatal adverse events occur. The latter very often influences the attitude towards immunization in our society and tends to result in resistance and refusal of its use in developed countries [3e5]. This behaviour can be observed after the successful disappearance of infectious diseases, when the benefit of further vaccination is no longer obvious [6]. This development is a major challenge in public health, as vaccine-preventable infectious diseases are re-emerging (e.g. measles in Switzerland [7]). An adverse event following immunization (AEFI) is defined as any untoward medical occurrence which follows immunization but which does not necessarily have a causal relationship with the usage of the vaccine [8]. An adverse event can be local or systemic; this includes symptoms like injection site reactions (e.g. pain, swelling), fever, fatigue, headache and joint pain. In rare cases, the adverse event can be serious such as an anaphylactic shock or death. Live vaccines can in rare cases lead to the manifestation of the disease (e.g. oral polio vaccine: vaccine induced polio or yellow fever: vaccine induced viscerotropic disease). Besides the active vaccine agent, other vaccine additives also can be responsible for the adverse event(s) [9], [Table 1]. The pharmacovigilance [10,11] is a very important component of immunization programs in order to guarantee the safety of new vaccines and to react quickly and
Table 1
Adverse reactiona
Immunizationb Serious adverse event or reactiona Side effecta Unexpected adverse reactiona Vaccineb a
Does the literature describe any sex-differences in the adverse event profile following human papilloma virus vaccine, MMR vaccine and hepatitis B vaccine vaccination? If yes, what are the differences? To what extent can they be attributed to specific causes, in order that recommendations can be derived?
Definitions of Terms (WHO and CDC).
Adverse eventa
b
adequately to new concerns. Passive surveillance is unable to determine the causal relationship between an adverse event following immunization. If a vaccine safety signal is generated by passive surveillance, further epidemiological studies are required in order to evaluate the likelihood of a causal relationship [12]. A review published in 2009 could already demonstrate that the pathophysiology of the sex-differences in local reactions following immunization was clearly multifactorial, with hypersensitivity reactions, route of administration and hormonal factors being suggested [13]. In another review by the same author [14] in comparative data he concluded, that intramuscular injection was associated with significantly lower rates of injection site reactions and a greater immune response than the subcutaneous route. The objective of this review is to analyse the adverse events reported with human papilloma virus vaccine, measlesemumpserubella vaccine and hepatitis B vaccine in children and adolescents by sex. Furthermore this review will analyse if there is a relationship between the current vaccination practice and the adverse event profile. New data from clinical studies can lead to changes in recommendations for the vaccination practice. For example the time schedule for MMR vaccination 1 and 2 has been modified based on clinical experience. The purpose of this analysis is to collate evidence to highlight and minimize sex specific adverse events following immunization (AEFI) and this evidence may be useful to guide practice in the future. The goals of this review are to address the following questions:
Medical occurrence temporally associated with the use of a medicinal product, but not necessarily causally related. A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or modifications of physiological function. The process by which a person or animal becomes protected against a disease. This term is often used interchangeably with vaccination or inoculation. Any untoward medical occurrence that at any dose results in death, is life threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation or results in persistent of significant disability or incapacity. Unintended effect occurring at normal dose related to the pharmacological properties. Not consistent with applicable product information or characteristics of drug. A product that produces immunity therefore protecting the body from the disease. Vaccines are administered through needle injections, by mouth and by aerosol.
WHO: http://www.who.int/medicines/areas/quality_safety/safety_efficacy/trainingcourses/definitions.pdf. CDC, Definition of terms: http://www.cdc.gov/vaccines/vac-gen/imz-basics.htm.
Please cite this article in press as: Weber SK, Schlagenhauf P, Childhood vaccination associated adverse events by sex: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.01.008
+
MODEL
Childhood vaccination associated adverse events by sex
Methods Literature search sources The Cochrane Database was searched using the terms: MeSH Human Papilloma Virus Vaccine e adverse effects MeSH MeasleseMumpseRubella Vaccine e adverse effects MeSH Hepatitis B Vaccines e adverse effects The Medline (Pubmed) Database was searched using the following terms: ((hpv/mmr/hepatitis b vaccine [MeSH Terms]) AND adverse events) AND (children and adolescents) ((hpv/mmr/hepatitis b vaccine [MeSH Terms]) AND adverse events) AND (girls and boys) The Embase Database was searched using the following terms: ‘human papilloma virus vaccine’/exp OR ‘human papilloma virus vaccine’ AND ‘adverse events’ AND ‘children and adolescents’ ‘human papilloma virus vaccine’/exp OR ‘human papilloma virus vaccine’ AND ‘adverse events’ AND (‘children’/exp OR ‘children’) ‘human papilloma virus vaccine’/exp OR ‘human papilloma virus vaccine’ AND ‘adverse events’ AND ‘adolescents’ ‘mmr vaccine’/exp OR ‘mmr vaccine’ AND ‘adverse events’ AND ‘children and adolescents’ ‘mmr vaccine’/exp OR ‘mmr vaccine’ AND ‘adverse events’ AND ‘children’ ‘mmr vaccine’/exp OR ‘mmr vaccine’ AND ‘adverse events’ AND ‘ adolescents’ ‘hepatitis b vaccines’/exp OR ‘hepatitis b vaccines’ AND ‘adverse events’ AND ‘children and adolescents’ ‘hepatitis b vaccines’/exp OR ‘hepatitis b vaccines’ AND ‘adverse events’ AND ‘children’ ‘hepatitis b vaccines’/exp OR ‘hepatitis b vaccines’ AND ‘adverse events’ AND ‘adolescents’ ‘human papilloma virus vaccine’/exp OR ‘human papilloma virus vaccine’ AND ‘adverse events’ AND ‘girls and boys’ ‘human papilloma virus vaccine’/exp OR ‘human papilloma virus vaccine’ AND ‘adverse events’ AND ‘girls’ ‘human papilloma virus vaccine’/exp OR ‘human papilloma virus vaccine’ AND ‘adverse events’ AND ‘boys’ ‘mmr vaccine’/exp OR ‘mmr vaccine’ AND ‘adverse events’ AND ‘girls and boys’ ‘mmr vaccine’/exp OR ‘mmr vaccine’ AND ‘adverse events’ AND ‘girls’ ‘mmr vaccine’/exp OR ‘mmr vaccine’ AND ‘adverse events’ AND ‘boys’ ‘hepatitis b vaccines’/exp OR ‘hepatitis b vaccines’ AND ‘adverse events’ AND ‘girls and boys’ ‘hepatitis b vaccines’/exp OR ‘hepatitis b vaccines’ AND ‘adverse events’ AND ‘girls’ ‘hepatitis b vaccines’/exp OR ‘hepatitis b vaccines’ AND ‘adverse events’ AND ‘boys’
3 The search was limited to articles published and accessible online up to December 31st 2012. There was no limit set for the beginning of the search. The first author identified articles that were possibly or highly likely to be relevant to the review, on the basis of the title and the abstract. The title and the abstract should contain or indicate information on adverse events following immunization in children and adolescents, if possible of both sexes, referring to the measlesemumpserubella vaccine, hepatitis B vaccine and human papilloma virus vaccine. This list was then reviewed by both authors who also agreed on which articles should be selected.
Extraction of items from the publication and inclusion criteria The following points listed below needed to be fulfilled in the title and abstract (which were supposed to be the minimum requirements), to identify publications for analysis. Reference: article, title, authors Abstract: Indicating relevance to the research objectives Purpose: according to the authors’ criteria for inclusion. These criteria are: Does the literature describe any sexdifferences in the adverse events following human papilloma virus vaccine, measlesemumpserubella vaccine and hepatitis B vaccine? Study designs: Study designs for inclusion in the review, if available: meta-analysis, systematic reviews, randomized clinical trials and other cohort studies. The reference lists of some of the systematic reviews were useful to identify some papers that did not come up in the search. Population: Demographic data (children and adolescents, males and females) Incident: adverse events after human papilloma virus vaccine, measlesemumpserubella vaccine and hepatitis B vaccine, not administered at the same time with other (combined) vaccines such as diphtheriaetetanusepertussis vaccine, diphtheriaetetanusepertussisehaemophilusepolio vaccine and other combined vaccines applied in children and adolescents. Control: Description of the control group or alternative intervention like application of another vaccine like e.g. hepatitis A vaccine or other vaccines. Outcome: Results of the incidence, sex-differences in the adverse event profile in children and adolescents, public health proposals and recommendations.
Results Data analysis Of the 417 publications retrieved from one or more of the three databases [Table 2], 89 (21%) were identified as being potentially relevant to the review, 41 (36.5%) were considered to satisfy the list of criteria for inclusion in this review.
Please cite this article in press as: Weber SK, Schlagenhauf P, Childhood vaccination associated adverse events by sex: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.01.008
+
MODEL
4
S.K. Weber, P. Schlagenhauf Table 2
Source database and number of publications.
Database
Cochrane
Pubmed
Embase
Read Inclusion Quoted Exclusion Read Inclusion Quoted Exclusion Read Inclusion Quoted Exclusion
Human papilloma virus vaccine
Measles mumps rubella vaccine
Hepatitis B vaccine
0 0 0 0 27 12 8 15 7 5 4 2
4 3 0 1 14 7 6 7 14 7 5 7
1 0 0 1 16 5 2 11 6 2 1 4
Read: Publications have been read, selected by information of the title and abstract, being potentially relevant for the review. Inclusion: Publications included for evaluation. Quoted: Discussed in the text. Exclusion: Publications excluded for evaluation because criteria were not met (did not fulfil the reporting of adverse events by age / sex).
Presentation of the results Adverse events following hepatitis B vaccine Of the 23 selected publications from the three databases, 16 were excluded because they did not fulfil the reporting of adverse events by sex. Of the 7 included papers for our evaluation, 2 reported adverse events only by age [15,16], while Niu et al. [17] was the only study to report on adverse events by different age groups and by sex. 4 publications [18e21] did not have sufficient information for further evaluations [Table 3]. The objective of Martins [15] et al. multicentre, doubleblind prospective study of 2754 subjects was to analyse the immunogenicity and safety of two recombinant vaccines (Butang and Engerix) against hepatitis B. In the children’s age group 1e10 years the results for seroprotection and geometric mean titres were maximal. This group showed the strongest immune response decreasing with age. No serious adverse events related to the vaccine were reported. In 13 cases adverse events following the previous dose led to withdrawal from the study, in only 2 cases there was a clear causal relationship to the vaccine (generalized pruritus in one adolescent and generalized urticaria in one adult). No further age- or sex-specific adverse events analyses were done. Fisher et al. [16] analysed NHIS (National Health Interview Survey) datasets to provide post-marketing surveillance data (probability samples) of infrequent adverse reactions to the hepatitis B vaccine. The authors investigated the association of the vaccine with adverse health outcomes in US children less than 6 years of age and addressed the lack of long-term follow-up after vaccination. Controlling the data simultaneously for race, age and gender, the risk of chronic arthritis, incident cases of pharyngitis/nasopharyngitis and incident cases of acute ear infections were for all 3 diagnoses always
higher among children 0e5 years old who received the vaccination than in children without vaccination. Although in the descriptive summary a distribution by gender has been done and the data were controlled by gender, there was no sex-specific analysis of adverse events. By reviewing case series from 1991 to 1994 of the national Vaccine Adverse Event Reporting System (VAERS), Niu et al. [17] evaluated the post marketing safety of recombinant hepatitis B vaccine given to neonates and infants in the U.S. Analysing the events in neonates and children by severity, no difference by gender could be observed. Fever was the most common serious symptom in neonates. Reported deaths were highest for neonates and infants compared to other age groups, while looking at the total number of adverse events and reported deaths, the rates were higher for male infants. Adverse events following measlesemumpserubella vaccine Of the 32 selected publications from the three databases, 15 were excluded because they did not fulfil the reporting of adverse events by age/sex. Of the 17 included papers for our evaluation, 8 authors reported adverse events by age [22e29], 1 by sex [30] and the remaining 2 by age and sex [31,32]. 6 publications [33e38] did not have sufficient information for further evaluations [Table 4]. The Finnish 14 year prospective follow-up study analysed through a passive surveillance system the causality of severe adverse events related to MMR vaccination [22]. 1.8 million individuals (the age at the time of vaccination ranged from 13 months to 23 years, the main target group being children at the age of 14e18 month and 6 years) received the vaccination, among these 173 potentially serious reactions were asserted to have been caused by the MMR vaccine: 77 neurologic ((febrile seizures in 52 vaccinees 49
