Update on the Recommended use of Hepatitis A Vaccine
Organization: Public Health Agency of Canada
Published: May 2016
Cat.: HP40-155/2016E-PDF
ISBN: 978-0-660-05284-7
Pub.: 160028
Related Topics
An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI)
Preamble
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (hereafter referred to as the Agency) with ongoing and timely medical, scientific, and public health advice relating to immunization. The Agency acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Agency's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Table of contents
Summary of information contained IN this NACI Statement
The following summary highlights key information for immunization providers. Please refer to the remainder of the Statement for details.
1. What
Immunization with Hepatitis A (HA) vaccine is recommended for pre-exposure immunization of persons at increased risk of infection or severe HA, as well as for post-exposure prophylaxis of: susceptible household and close contacts of proven or suspected cases of HA; co-workers and clients of infected food handlers; and staff and attendees of group child care centres and kindergartens when HA has occurred in them.
2. Who
For pre-exposure immunization, immunization with HA vaccine may be provided to persons six months of age and older.
For post-exposure prophylaxis, unless contraindicated or unavailable, HA vaccine is recommended in preference to Ig for individuals six months of age and older.
Immunization with HA vaccine may be considered for all individuals receiving repeated replacement of plasma-derived clotting factors.
3. How
For post-exposure prophylaxis within 14 days of exposure of susceptible adults 60 years of age and older who are household or close contacts of a case, Ig may be provided in addition to HA vaccine.
For post-exposure prophylaxis of susceptible individuals with chronic liver disease, Ig should be provided within 14 days of exposure in addition to HA vaccine.
4. Why
The severity of HA increases with age. Children less than six years of age are commonly asymptomatic or present with mild disease without jaundice, and represent an important source of infection, particularly for household members and other close contacts. In older children and adults, HA is typically symptomatic. Older persons, and individuals with chronic liver disease and immunocompromising conditions, have an increased risk of progressing to fulminant hepatic failure resulting in death.
I. Introduction
NACI currently recommends pre-exposure immunization of persons at increased risk of infection or severe hepatitis A (HA) infection as defined in the Canadian Immunization Guide (CIG). Although not authorized for children less than 12 months of age in Canada, HA vaccine has previously been used in some First Nations communities starting at 6 months of age and in infants travelling to high risk areas.
For post-exposure prophylaxis, NACI recommends that HA vaccine should be offered to household and close contacts of proven or suspected cases of HA, as well as co-workers and clients of infected food handlers and staff and attendees of group child care centres and kindergartens when HA has occurred in them. NACI recommends the use of human immune globulin (Ig) in circumstances when protection against hepatitis A infection is required in addition to or in the absence of immunization with HA vaccine. Specific HA antibody content in Ig is not regulated by Health Canada and therefore concentrations of HA antibody may be declining due to lower levels of antibody in the general population as a result of decreased rates of natural infection.
This statement will serve as an update to previous statements and will provide the evidence used to determine the optimal timing of immunization with a HA containing vaccine by:
- Providing a review of the evidence on the immunogenicity and safety of HA vaccine when administered to infants from 6 to 12 months of age and making recommendations for the immunization of individuals in this age group
- Reviewing evidence pertaining to the administration of HA vaccine to individuals with non-malignant hematologic disorders
- Reviewing evidence pertaining to post exposure prophylaxis (PEP) in individuals with chronic liver disease and adults over 50 years of age
II. Methods
The NACI Hepatitis Working Group (HWG) reviewed key issues concerning the currently recommended immunization schedules for HA-containing vaccines approved for use in Canada, with particular consideration given to immunogenicity and safety when a HA-containing vaccine was provided to infants between 6 and 12 months of age. Under HWG supervision, knowledge synthesis was performed by a medical advisor at the Agency. Using key words "hepatitis A" AND "vaccine", studies evaluating safety, immunogenicity and efficacy in infants immunized between 6 and 12 months of age with an inactivated HA-containing vaccine were assessed. Following the critical appraisal of individual studies, summary tables with ratings of the quality of the evidence were prepared using NACI's methodological hierarchy (Tables 6 and 7).
NACI reviewed such considerations as: the target population; safety, immunogenicity, efficacy, effectiveness of the vaccines; vaccine schedules; and other aspects of the overall immunization principles and strategy for the use of this vaccine. NACI HWG Chair and an Agency medical advisor presented the evidence and proposed recommendations to NACI. Following the review of the evidence and consultation at the NACI meeting on February 4, 2015, the committee voted on specific recommendations. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the text of this update.
III. Epidemiology of hepatitis A
Mean Annual Incidence Rate (2006-2012)Table 1 footnote 1 per 100,000 population |
Mean Annual Hospitalization Rate (2006-2010)Table 1 footnote 2 |
Mean Case Fatality Rate (2006-2010)Table 1 footnote 3 |
|
---|---|---|---|
<1 year | 0.43 | 0% | 0% |
1-4 years | 1.62 | 16% | 0% |
5-9 years | 2.24 | 12% | 0% |
10-14 years | 1.61 | 27% | 0% |
15-19 years | 1.23 | 24% | 0% |
20-24 years | 1.24 | 19% | 0% |
25-29 years | 1.02 | 18% | 0% |
30-39 years | 0.81 | 26% | 0% |
40-59 years | 0.57 | 31% | 0.94% |
60+ years | 0.65 | 30% | 2.20% |
Total | 0.94 | 24% | 0.49% |
|
2006 | 2007 | 2008 | 2009 | 2010 | 2011 | 2012 | Total | |
---|---|---|---|---|---|---|---|---|
<1 year | 2 | 1 | 3 | 0 | 1 | 2 | 2 | 11 |
1-4 years | 37 | 15 | 21 | 12 | 19 | 35 | 26 | 165 |
5-9 years | 72 | 31 | 38 | 26 | 33 | 52 | 30 | 282 |
10-14 years | 67 | 34 | 23 | 22 | 22 | 29 | 30 | 227 |
15-19 years | 31 | 22 | 26 | 17 | 29 | 39 | 28 | 192 |
20-24 years | 38 | 20 | 26 | 25 | 33 | 35 | 22 | 199 |
25-29 years | 29 | 25 | 23 | 22 | 23 | 24 | 18 | 164 |
30-39 years | 62 | 28 | 35 | 46 | 37 | 30 | 19 | 257 |
40-59 years | 94 | 65 | 56 | 58 | 47 | 42 | 37 | 399 |
60+ years | 44 | 56 | 47 | 48 | 32 | 36 | 34 | 297 |
Total | 476 | 297 | 298 | 276 | 276 | 324 | 246 |
IV. Vaccines
IV.1 Efficacy and effectiveness
No studies on the efficacy or effectiveness of HA-containing vaccines in children 6 to 12 months of age were identified through the literature search.
IV.2 Immunogenicity
A total of eight studies that included participants less than one year of age were reviewed by HWG and NACI. A full review of all studies, their methodologies and outcome measures, can be found in Table 3a. Additionally, two confidential Clinical Study Report (CSR) synopses were also provided by the vaccine manufacturer. Information from the reviewed CSR synopses was determined to be consistent with the other published data reviewed by the HWG.
Review of all immunogenicity studies, their methodologies and outcome measures can be found in Tables 3a, 4 and 5.
IV.3 Safety
Safety data for HA vaccine in infants 6 to 12 months of age were obtained from six of the reviewed studies. A review of these studies, their methodologies and outcome measures can be found in Table 3b. Additional information that was obtained from two confidential CSR synopses provided by a vaccine manufacturer was consistent with other reviewed studies. A supplementary safety-relevant data analysis available through the Agency did not indicate any safety concerns with HA vaccine at any age. Fewer than 10 reports involving infants 6 to 12 months of age were submitted to the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) from January 2011 to June 2014, with most including a HA-containing vaccine co-administered with routine infant vaccines. However, it is important to note that the actual number of individuals who were immunized in this age group is not known and therefore the data obtained through CAEFISS must be interpreted with caution.
Similar to the safety and reactogenicity of HA vaccines in older subjects, the most frequently reported adverse event in infants 6 to 12 months of age was injection site reaction, with the majority of symptoms described as mild or moderate and resolving within 1 to 2 days after vaccination.
V. Recommendations
Comparable to the results reported in clinical trials of children more than 12 months of age, all reviewed studies have consistently shown that vaccination of infants 6 to 12 months of age with inactivated HA vaccines is immunogenic and safe. Following the receipt of two doses, seroprotection (as defined by study authors) was achieved, independent of age, schedule used or initial HA serological status. When the vaccine was provided to seronegative infants, immune response and long-term antibody levels were comparable to those achieved following immunization at an older age. In all infants born to seropositive mothers, despite lower antibody levels that were observed following immunization, booster vaccination elicited a robust anamnestic response, suggesting good priming and an established immune memory potential despite maternal antibody interference. However, because of very low rates of anti-HA seropositivity as a result of natural infection among women of reproductive age in Canada, potential concerns regarding maternal antibody interference are likely not to represent a significant issue. Recommendations 1 to 3 pertain to products which have been approved for use in children one year of age.
Recommendation 1: HA vaccine may be provided, beginning at six months of age, to infants who are at increased risk of infection or severe HA. (NACI recommendation Grade B)
Infants at increased risk of severe HA infection may include those with an underlying liver disease of idiopathic, metabolic, infectious or cholestatic etiology. Canadian-born infants travelling to HA endemic countries, including children of new Canadians returning to their country of origin to visit friends and relatives, may be at increased risk of HA infection.
Recommendation 2: HA vaccine may be provided to infants beginning at six months of age, who are living in a household with an individual who is at increased risk of infection or severe HA. (NACI recommendation Grade B)
Recommendation 3: For post-exposure prophylaxis, unless contraindicated or unavailable, HA vaccine is recommended in preference to Ig for healthy individuals six months of age and older. (NACI recommendation Grade B)
Because the HA antibody content of Ig is assumed to decrease over time as a result of lower population-level antibody levels (due to lower rates of natural infection), and because of an excellent safety profile of inactivated HA-containing vaccine, immunization is preferred over the administration of a blood-derived product.
Recommendation 4: Immunization with HA vaccine may be considered for all individuals receiving repeated replacement of plasma-derived clotting factors. (NACI recommendation Grade I)
The solvent-detergent (S/D) method used to prepare plasma-derived clotting factor concentrates does not reliably inactivate the HA virus. However, historically there has been no evidence of HA transmission from plasma-derived clotting factor in Canada and the risk of transfusion-related HA is extremely low because all pooled plasma is tested for HA. Due to a theoretical possibility of infection, immunization of individuals receiving large quantities of plasma-derived clotting factors may be considered. In Canada, product monographs of all S/D plasma-derived products used in the treatment of conditions requiring clotting factor substitution include recommendations for HA immunization.
Recommendation 5: For post-exposure prophylaxis within 14 days of exposure of susceptible adults 60 years of age and older who are household or close contacts of a case, Ig may be provided in addition to HA vaccine. (NACI recommendation Grade I)
Individuals without a history of disease or previous immunization are susceptible to HA infection. Evidence is suggestive of reduced immunogenic response to HA vaccine, as well as of higher HA infection-related hospitalization and case fatality rates with increasing age. However, due to significant uncertainty about the incremental value of passive immunization on disease outcomes, (including Ig HA antibody content), high HA antibody prevalence in older age groups and a small number of cases of HA infection-related complications in individuals over 60 years of age, the decision to include Ig for post-exposure HA prophylaxis should be made on a case-by-case basis. Given the lack of data to support benefit of Ig after 14 days, there is no recommendation for its use after this time period. Post exposure prophylaxis with vaccine alone is recommended for outbreak response.
Recommendation 6: For post-exposure prophylaxis of susceptible individuals with chronic liver disease, Ig should be provided within 14 days of exposure in addition to HA vaccine. (NACI recommendation Grade B)
Because of the risk of severe disease and a suboptimal immune response to HA vaccine among individuals who are immunocompromised and with chronic liver disease, Ig is recommended to provide immediate protection against HA infection until an active response to the vaccine is produced. Given the lack of data to support benefit of Ig after 14 days, there is no recommendation for its use after this time period.
VI. Surveillance and research priorities
- Enhanced epidemiological surveillance that can provide information about the incidence of HA infection, stratified by risk factors and age group, as well as data on post exposure management of HA cases and contacts.
- Enhanced safety surveillance of immunized infants less than one year of age.
- Studies on long-term protection, including antibody duration and persistence of immune memory.
- Studies on post-exposure efficacy and vaccine failure or breakthrough of disease following the receipt of one vs. two vaccine doses.
- Studies to determine the importance of post-immunization titres and anti-HAV antibody waning in protection against clinical infection.
- Studies on efficacy of Ig used in Canada for the prevention of HA.
Tables
Study Details | Summary | |||||
---|---|---|---|---|---|---|
Study | Vaccine | Study Design | Participants | Summary of Key Findings and Outcome Data | Level of Evidence | Quality |
Bell BP, Negus S, Fiore AE, Plotnik J, Dhotre KB, Williams J, Shapiro CN, McMahon BJ. Immunogenicity of an inactivated hepatitis A vaccine in infants and young children. Pediatr Infect Dis J. 2007 Feb;26(2):116-22.Reference 15 |
HAVRIX® Other infant vaccines provided at 6 months of age: |
Phase IV RCT Alaska, US Seropositive defined as titer ≥33 mIU/ml Antibody status determined at the time of first vaccine dose (baseline) and at 1, 7 and 12 months thereafter. All children tested at age 13 months for responses to recommended routine vaccinations |
N=248 enrolled Group 1 (n=82): vaccinated at ages 6 and 12 months Group 2 (n=83): vaccinated at ages 12 and 18 months Group 3 (n=78): vaccinated at ages 15 and 21 months (control) HA vaccine administered with other age-appropriate infant vaccines 79% of study participants were full or part Alaska Native |
All participants in all groups seropositive following dose 2 except Group 1 infants born to immune mothers (94%; 34/36). No statistically significant differences in GMC at any point between Groups 3 and either Group 2 or Group 1 in children born to anti-HAV-negative mothers. Statistically significant differences in GMC at all times between Groups 1 and Group 2 or Group 3 in children born to anti-HAV-positive mothers (p<0.05) / No difference observed in responses to routinely administered vaccines. Infants born to anti-HA-positive mothers Infants born to anti-HA-negative mothers |
Level I |
Fair |
Lagos R, Munoz A, R. Dumas, S. Pichon, B. Zambrano, M. Levine, E. Vidor |
AvaximTM pediatric, Aventis Pasteur, Other infant vaccines provided at 6 months of age: Other infant vaccines provided at 12 months of age: |
Phase II open descriptive study Santiago, Chile Seropositivity defined as titer ≥20 mIU/ml |
N=103 enrolled Group 1: vaccinated at ages 6.5 and 12 months (2 weeks following routine vaccination at 6 months) Group 2: vaccinated at ages 6 and 12 months concomitantly with routine vaccination |
88% seropositive at inclusion Group 1; n=43 (% seropositive infants; GMT mIU/mL (95% CI)) : Group 2; n=48 (% seropositive infants; GMT mIU/mL (95% CI)) : Pre/post booster immunization GMT ratio of over 22 observed in both groups. |
Level III |
Poor |
López EL, Contrini MM, Xifró MC, Cattaneo MA, Zambrano B, Dumas R, Rouyrre N, Weber F. Hepatitis A vaccination of Argentinean infants: comparison of two vaccination schedules. Vaccine. 2007 Jan 2;25(1):102-8. Epub 2006 Jul 28.Reference 20 |
AvaximTM pediatric, Aventis Pasteur, |
Phase II RCT Buenos Aires, Argentina Seropositivity defined as titer ≥20 mIU/ml |
N=131 enrolled Group 1: three doses at 2, 4, 6 months of age and booster dose at 15-18 months Group 2: one dose at 6 months of age and booster dose at 15-18 months |
Seronegative prior to immunization Group 2; n=5 (% seropositive infants; GMC mIU/mL (95% CI)) : Seropositive prior to immunization Group 2; n=55 (% seropositive infants; GMC mIU/mL (95% CI)) : |
Level I |
Fair |
Nolan T, Bernstein H, Blatter MM, Bromberg K, Guerra F, Kennedy W, Pichichero M, Senders SD, Trofa A, Collard A, Sullivan DC, Descamps D. Immunogenicity and safety of an inactivated hepatitis A vaccine administered concomitantly with diphtheria-tetanus-acellular pertussis and haemophilus influenzae type B vaccines to children less than 2 years of age. Pediatrics. 2006 Sep;118(3):e602-9.Reference 22 |
HAVRIX®, GSK Biologicals, Other infant vaccines provided according to schedule: |
Open, nonrandomized, 70% of Seropositivity defined as antibody titer >15 mIU/mL Seroresponse Anti-HAV GMC between groups considered equivalent if 95% CI included within protocol defined limits of [0.5; 2.0]. |
N=1084 enrolled Group 1 (11-13 mo): 2 doses of HAV vaccine 6 months apart Group 2 (15-18 mo): 2 doses of HAV vaccine 6 months apart Group 3 (15-18 mo): 2 doses of HAV vaccine 6 months apart and 1 dose of DTaP, and Hib at month 0 Group 4 (15-18 mo): DTaP, and Hib at month 0, and 2 doses of HAV vaccine at months 1 and 7 Group 5 (23-25 mo): 2 doses of HAV vaccine 6 months apart |
Group 1; n=218 (% seropositive infants; GMC mIU/mL (95% CI)) : Group 2; n=200 (% seropositive infants; GMC mIU/mL (95% CI)) : Group 3; n=131 (% seropositive infants; GMC mIU/mL (95% CI)) : Group 4; n=115 (% seropositive infants; GMC mIU/mL (95% CI)) : Group 5; n=211 (% seropositive infants; GMC mIU/mL (95% CI)) : One month after dose 2: 100%; 1910.7 Equivalence of anti-HAV GMCs in responders after the first dose of HAV vaccine (secondary study objective) demonstrated between Group 1 and Group 5 (GMC ratio: 0.62; 95% CI: 0.51-0.75) |
Level II-1 |
Fair |
Sharapov UM, Bulkow LR, Negus SE, Spradling PR, Homan C, Drobeniuc J, Bruce M, |
HAVRIX®, Glaxo SmithKline Biologicals; |
Phase IV RCT Alaska, US Seropositivity defined as titer ≥10 mIU/ml Antibody status determined 1 and 6 months after dose 2, and at 3, 5, 7 and 10 years of age. |
N=197 available for follow-up study; n=82 received HA vaccine at 6 months of age Group 1: infants vaccinated at ages 6 and 12 mo; Group 2: infants vaccinated at ages 12 and 18 mo; Group 3: infants (control) vaccinated at ages 15 and 21 mo. HA vaccine administered with other age-appropriate infant vaccines 96% of study participants were full or part Alaska Native |
In group 1, all children born to anti-HAV-negative mothers remained seropositive through 3 years. At year 5, 7, and 10 seroprotection was lost in 3%, 5%, and 7% of children. All children in Group 2 and 3 remained seropositive during 10 years of follow-up. Consistently lower GMC values between Group 1 and Group 2 or 3; statistically significant difference only in children born to anti-HAV-positive mothers. Lower GMC values in children born to anti-HAV-positive mothers in all groups; significant only for the first three time periods. Infants born to anti-HA-positive mothers Infants born to anti-HA-negative mothers |
Level I |
Fair |
Stojanov S, Liese JG, Belohradsky BH, Vandermeulen C, Hoppenbrouwers K, Van der Wielen M, Van Damme P, Georges B, Dupuy M, Scemama M, Watson M, Fiquet A, Stek JE, Golm GT, Schödel FP, Kuter BJ; HEXAVAC/VAQTA Study Group. Administration of hepatitis A vaccine at 6 and 12 months of age concomitantly with hexavalent (DTaP-IPV-PRP approximately T-HBs) combination vaccine. Vaccine. 2007 Oct 23;25(43):7549-58. Epub 2007 Sep 4.Reference 18 |
VAQTA, Merck, 25 IU/dose Hexavalent (HV) vaccine: |
Open, multicenter, RCT Belgium and Germany Seropositivity defined as titer ≥10 mIU/ml Baseline seropositivity determined at 2 months of age |
N=619 Group 1 (separate): HV vaccine at 2, 4, 6, and 12 months of age and one dose of the HA vaccine at 7 and 13 months of age. Group 2 (concomitant): HV vaccine at 2, 4, 6, and 12 months of age and one dose of the HA vaccine at 6 and 12 months of age. |
Seronegative infants Group 1; n=153 ((% seropositive infants; GMT in mIU/mL): Group 2; n=145 ((% seropositive infants; GMT in mIU/mL): Seropositive infants Group 1; n=80 ((% seropositive infants; GMT in mIU/mL): Group 2; n=80 ((% seropositive infants; GMT in mIU/mL): |
Level I |
Fair |
Usonis V, Bakasenas V, R. Valentelis, G. Katiliene, D. Vidzeniene, C. Herzog |
Epaxal, Berna Biotech Ltd., ≥500 RIA (radioimmunoassay) units of HAV antigen; |
Open, uncontrolled, single-centre pilot study Lithuania Seropositivity defined as titer ≥20 mIU/ml |
N=60 Group 1 (infants): Group 2 (children): |
Seropositive infants Group 1; n=16 (% seropositive infants; GMT mIU/mL (95% CI)) : Seronegative infants Group 1; n=14 (% seropositive infants; GMT in mIU/mL (95% CI)): Group 2; n=30 (% seropositive infants; GMT in mIU/mL): |
Level III |
Fair |
Letson GW, Shapiro CN, Kuehn D, Gardea C, Welty TK, Krause DS, et al. Effect of maternal antibody on immunogenicity of hepatitis A vaccine in infants. J Pediatr 2004;144(3:327-32.Reference 19 |
HAVRIX®, Glaxo SmithKline Biologicals; 360 EL.U/ per dose; HB vaccine |
Prospective, randomized, single-blinded USA American Indian infants Seropositivity defined as titer ≥20 mIU/ml |
N=123 Group 1 Group 2 Group 3 |
Results for only 12 infants in Group 3 available at 15 months of age follow-up; 9 (75%) had seroprotective levels before first dose. No statistically significant difference post immunization between antibody levels among infants with and without protective antibody levels at the time of initial HA vaccine administration. |
Level I |
Poor |
Study details | Summary | |||||
---|---|---|---|---|---|---|
Study | Vaccine | Study Design | Participants | Summary of Key Findings Using Text or Data | Level of Evidence | Quality |
Bell BP, Negus S, Fiore AE, Plotnik J, Dhotre KB, Williams J, Shapiro CN, McMahon BJ. Immunogenicity of an inactivated hepatitis A vaccine in infants and young children. Pediatr Infect Dis J. 2007 Feb;26(2):116-22.Reference 15 |
HAVRIX® Other infant vaccines provided at 6 months of age: |
Phase IV Alaska, US Pain, redness or swelling at any injection site and fever, indications of irritability or other changes in behavior or any illness noted for 3 days after vaccination |
N=248 enrolled; Group 1 infants vaccinated at ages 6 and 12 mo; Group 2 infants vaccinated at ages 12 and 18 mo; Group 3 infants (control) vaccinated at ages 15 and 21 mo HA vaccine administered with other age-appropriate infant vaccines 79% of study participants were full or part Alaska Native |
The most frequently reported solicited adverse events were pain at the injection site (20-32%), sleepiness (17-34%) and fussiness (18-30%); majority of symptoms resolved within 1 to 2 days after vaccination. Fever of 1 day's duration was reported by 12% of participants after either vaccine dose; fever of at least 3 days' duration was uncommon (0-6%). No differences between three groups were reported. |
Level I |
Fair |
López EL, Contrini MM, Xifró MC, Cattaneo MA, Zambrano B, Dumas R, Rouyrre N, Weber F. Hepatitis A vaccination of Argentinean infants: comparison of two vaccination schedules. Vaccine. 2007 Jan 2;25(1):102-8. Epub 2006 Jul 28.Reference 20 |
AvaximTM pediatric, Aventis Pasteur, |
Phase II RCT Buenos Aires, Argentina Local and systemic reactions and events recorded daily during the 7 days after injections. All medical events occurring within 28 days after the vaccinations were listed, and serious adverse events were reported whenever they occurred during the entire duration of the study. |
N=131 infants; n=59 primed only at 6 months of age Group 1: three doses at 2, 4, 6 months of age and booster dose at 15-18 months Group 2: one dose at 6 months of age and booster dose at 15-18 months |
Pain at injection site was the most frequent local reaction in both groups, reported for 42 subjects (42 of 59 events). Rates of local reactions were similar in Groups 1 and 2 after the booster injection, 14.5% and 12.5%, respectively. Except for one case of severe pain in each group after both the first injection and the booster, all local reactions were described as mild or moderate. Fever was the most common systemic reaction in both groups, in 14.8-25.8% in Group 1 and 11.5-17.5% in Group 2 for primary doses. |
Level I |
Fair |
Nolan T, Bernstein H, Blatter MM, Bromberg K, Guerra F, Kennedy W, Pichichero M, Senders SD, Trofa A, Collard A, Sullivan DC, Descamps D. Immunogenicity and safety of an inactivated hepatitis A vaccine administered concomitantly with diphtheria-tetanus-acellular pertussis and haemophilus influenzae type B vaccines to children less than 2 years of age. Pediatrics. 2006 Sep;118(3):e602-9.Reference 22 |
HAVRIX®, GSK Biologicals, Other infant vaccines provided according to schedule: |
Open, nonrandomized, multicenter study with allocation based on age and previous vaccination history 70% of the study population from US Solicited local AEs included pain, swelling, and redness at the injection site(s) during 3 days following immunization. Solicited general (systemic) AEs included drowsiness, fever (rectal body temperature >38.0°C), irritability, and loss of appetite during 3 days following immunization. All unsolicited AEs that occurred within 1 month after each dose of vaccine were recorded irrespective of severity or causal relationship to vaccination. |
N=1084 enrolled; n=243 in group 11-13 mo of age (Group 1) Group 1 (11-13 mo): 2 doses of HAV vaccine 6 months apart Group 2 (15-18 mo): 2 doses of HAV vaccine 6 months apart Group 3 (15-18 mo): 2 doses of HAV vaccine 6 months apart and 1 dose of DTaP, and Hib at month 0 Group 4 (15-18 mo): DTaP, and Hib at month 0, and 2 doses of HAV vaccine at months 1 and 7 Group 5 (23-25 mo): 2 doses of HAV vaccine 6 months apart |
Redness most frequently occurring solicited local AE in Group 1. Rates of grade 3 injection-site AEs low and comparable in both groups. Most frequently occurring solicited general AE for all of the groups was irritability (46.5% in Group 1). Rates of grade 3 solicited general AEs were low (0.8% in Group 1). |
Level II-1 |
Fair |
Stojanov S, Liese JG, Belohradsky BH, Vandermeulen C, Hoppenbrouwers K, Van der Wielen M, Van Damme P, Georges B, Dupuy M, Scemama M, Watson M, Fiquet A, Stek JE, Golm GT, Schödel FP, Kuter BJ; HEXAVAC/VAQTA Study Group. |
VAQTA, Merck & Co, 25 EL.U/ per dose Hexavalent (HV) vaccine provided according to schedule: |
Open, randomized, multicenter study Belgium and Germany Injection-sitepain, redness, swelling and warmth were reported but not measured; other injection-site reactions were spontaneously reported through 4 days post-dose. Rectal temperatures were recorded through 4 days after each dose of vaccine; other unsolicited adverse events were recorded through 14 days post-dose. Any serious and/or related adverse event occurring from 15 days after all vaccinations until 30 days after the last dose, until the next vaccination, or until the last study visit, was also recorded. |
N=619 Group 1 (separate): Group 2 (concomitant): |
The observed incidence of injection-site reactions at the HA vaccine site was generally similar between the two groups (8.9% versus 10.0%following dose 1 and 7.1% versus 12.5% following dose 2 in Groups 1 versus 2, respectively). After the 6-month visit, systemic events were reported by 39.9% of subjects in Group 1 and 42.7% in Group 2. After the 12-month visit, systemic events were reported by 43.0% of subjects in Group 1 and 41.7% in Group 2. Overall, within 14 days after the first three vaccination visits, fever was reported in 21.8% of subjects in Group 1 and 21.3% in Group 2. After the 12-month visit, 34.2% of subjects in Group 1 and 30.2% in Group 2 reported fever. HA vaccine was administered alone only at the 7- and 13-month visits, after which 22.1% and 22.9% of subjects, respectively, reported fever. |
Level I |
Fair |
Usonis V, Bakasenas V, R. Valentelis, G. Katiliene, D. Vidzeniene, C. Herzog |
Epaxal, Berna Biotech Ltd., ≥500 RIA (radioimmunoassay) units of HAV antigen; |
Open, uncontrolled, single-centre pilot study Lithuania Solicited local and systemic reactions, including pain/tenderness, swelling/tumefaction, hardness/induration, redness > 5 mm, fatigue, loss of appetite and temperature (all subjects), headache, nausea, and arthralgia (children), and persistent crying and irritability (infants) recorded throughout 4-day period. Unsolicited reported and observed adverse events documented by investigators at baseline and at 1, 12 and 13 months. |
N=60 Group 1 (infants): Group 2 (children): |
In both children and infants, the most commonly reported solicited local events were pain/tenderness (up to 14.7%) and swelling/tumefaction (up to 7.4%). In one infant and one child, the body temperature increased above 38.5 ◦C after primary vaccination, none after booster vaccination. |
Level III |
Fair |
Letson GW, Shapiro CN, Kuehn D, Gardea C, Welty TK, Krause DS, et al. Effect of maternal antibody on immunogenicity of hepatitis A vaccine in infants. J Pediatr 2004;144(3):327-32.Reference 19 |
HAVRIX®, Glaxo SmithKline Biologicals; 360 EL.U/ per dose; HB vaccine |
Prospective, randomized, single-blinded clinical USA American Indian infants Seropositivity defined as titer ≥20 mIU/ml |
Group 1 Group 2 Group 3 |
The frequency of adverse events was exceedingly rare (<1%; data not shown).There were no serious adverse events associated with any of the vaccines used during the study. |
Level I |
Poor |
Study details | Summary | |||||
---|---|---|---|---|---|---|
Study | Vaccine | Study Design | Participants | Summary of Key Findings and Outcome Data | Level of Evidence | Quality |
D'Acremont V, Herzog C, Genton B. Immunogenicity and safety of a virosomal hepatitis A vaccine (Epaxal®) in the elderly. J Travel Med. 2006;13(2):78-83.Reference 23 |
Epaxal, Berna Biotech Ltd. |
Open, uncontrolled, single-centre study Switzerland Seropositivity defined as titer ≥20 mIU/ml Antibody status determined 1 week before and 1, 6 and 12 months after initial vaccination, and 1 month after the second dose |
N=90 Groups 1: Group 2: |
Group 1 (% seropositive, GMT in mIU/mL (95% CI)): Group 2 (% seropositive, GMT in mIU/mL (95% CI)): When subdivided by age groups 31 to 45 years (n=11), 50 to 60 years (n=16) and >60 years (n=14), differences in GMT values at all time points and seroprotection at 6, 12 and 13 months were not significant between subgroups When lower threshold of 10 IU/mL was applied, all the subjects aged 50 t 60 years and 93% of subjects aged >60 years were seroprotected at 1 month |
Level II-1 |
Poor |
Briem H, Safary A. Immunogenicity and safety in adults of hepatitis A virus vaccine administered as a single dose with a booster 6 months later. J Med Virol. 1994;44(4):443-5.Reference 25 |
Inactivated hepatitis A vaccine, SmithKline Beecham Biologicals; IM, deltoid |
Open, uncontrolled, single-centre study Iceland Seropositivity defined as titer ≥20 mIU/ml Antibody status determined 1-2 weeks before and 2 weeks, 1, 6 and 7 months after initial vaccination |
N=200 Group 1 (n=134): Group 2 (n=66): Vaccine provided at 0 and 6 months |
Group 1 (% seropositive, GMT in mIU/mL): Group 2 (% seropositive, GMT in mIU/mL): Seropositivity rates significantly higher in group 1 only at day 15 (p < 0.05). |
Level III |
Poor |
Scheifele DW, Bjornson GJ. Evaluation of inactivated hepatitis A vaccine in Canadians 40 years of age or more. CMAJ. 1993 [cited 2013 Oct 18];148(4):551-5.Reference 24 |
Inactivated hepatitis A vaccine, SmithKline Beecham Biologicals; IM, deltoid |
Open, uncontrolled, single-centre study Canada Seropositivity defined as titer ≥20 mIU/ml Antibody status determined 2 weeks before and 1, 2, 6 and 7 months after initial vaccination |
N=64 Healthy adults 40 to 61 years of age Vaccine provided at 0, 1 and 6 months |
Seroconversion (titer ≥20 mIU/ml) occurred in 89% of study participants after dose 1. All study participants achieved protective antibody levels after dose two and remained seropositive at 6 months (before dose 3). |
Level III |
Fair |
Study details | Summary | |||||
---|---|---|---|---|---|---|
Study | Vaccine | Study Design | Participants | Summary of Key Findings and Outcome Data | Level of Evidence | Quality |
Keeffe EB, Iwarson S, McMahon BJ, Lindsay KL, Koff RS, Manns M, et al. Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease. Hepatology. 1998;27(3):881-6.Reference 26 |
HAVRIX®, Glaxo SmithKline Biologicals; 1440 EL.U/ per dose; IM, deltoid HBV |
Open, prospective, comparative, 8-centre study United States and Europe Antibody status determined prevaccination and at months 1, 2, 6, and 7 post immunization Seroconversion defined as titer ≥33 mIU/mL in previously seronegative individuals |
N=392 Group 1 (n=185): Group 2 (n=43): Group 3 (n=99): Group 4 (n=65): HA vaccine at months 0 and 6 HB vaccine at months 0, 1 and 6 |
Group 1 (% seropositive, GMC in mIU/mL (95%CI)): Group 2 (% seropositive, GMC in mIU/mL (95%CI)): Group 3 (% seropositive, GMC in mIU/mL (95%CI)): Group 4 (% seropositive, GMC in mIU/mL (95%CI)): Statistically higher seroconversion in healthy adults compared to individuals in Groups 3 and 4 after the first dose of HA vaccine. Statistically higher GMC values in healthy adults compared to Groups 2, 3 and 4 at all time points. |
Level II-1 |
Fair |
Dumot JA, Barnes DS, Younossi Z, Gordon SM, Avery RK, Domen RE, et al. Immunogenicity of hepatitis A vaccine in decompensated liver disease. Am J Gastroenterol. 1999;94(6):1601-4.Reference 27 |
HAVRIX®, Glaxo SmithKline Biologicals; 1440 EL.U/ per dose. IM, deltoid |
Open, prospective, one-centre study United States Antibody status determined at months 2 and 4 post immunization Seropositivity defined as titer ≥33 mIU/mL |
N=24; 8 liver transplant patients and 14 liver failure patients HA vaccine at months 0 and 2 |
The median antibody titer at 2 months was lower (p= 0.01) in liver transplant patients, 0.0 mIU/ml (range 0-4.0) compared to liver failure patients 33.5 mIU/ml (range 0 to 528.0). The rate of seroconversion was lower (p= 0.02) in liver transplant recipients (0/8) patients compared to the liver failure patients (7/14) |
Level III |
Poor |
Ferreira CT, da Silveira TR, Vieira SM, Taniguchi A, Pereira-Lima J. Immunogenicity and safety of hepatitis A vaccine in children with chronic liver disease. Journal of pediatric gastroenterology and nutrition 2003;37(3):258-61.Reference 28 |
HAVRIX®, Glaxo SmithKline Biologicals; 720 EL.U/ per dose. IM, deltoid |
Open, prospective, control study Brazil Antibody status determined at months 1 and 7 post initial immunization Seropositivity defined as titer ≥15 mIU/mL |
N=89 Group 1 (n=34): Group 2 (n=55): HA vaccine at months 0 and 6 |
Group 1 (% seropositive, GMT in mIU/mL (95%CI)): Group 2 (% seropositive, GMT in mIU/mL (95%CI)): |
Level II-1 |
Poor |
Level | Description |
---|---|
I | Evidence from randomized controlled trial(s). |
II-1 | Evidence from controlled trial(s) without randomization. |
II-2 | Evidence from cohort or case-control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy. |
II-3 | Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence. |
III | Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees. |
Quality Rating | Description |
---|---|
Good | A study (including meta-analyses or systematic reviews) that meets all design- specific criteriaTable 7 footnote * well. |
Fair | A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterionTable 7 footnote * but has no known "fatal flaw". |
Poor | A study (including meta-analyses or systematic reviews) that has at least one design-specificTable 7 footnote * "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations. |
|
Grade | Recommendation |
---|---|
A | NACI concludes that there is good evidence to recommend immunization. |
B | NACI concludes that there is fair evidence to recommend immunization. |
C | NACI concludes that the existing evidence is conflicting and does not allow making a recommendation for or against immunization; however other factors may influence decision-making. |
D | NACI concludes that there is fair evidence to recommend against immunization. |
E | NACI concludes that there is good evidence to recommend against immunization. |
I | NACI concludes that there is insufficient evidence (in either quantity and/or quality) to make a recommendation, however other factors may influence decision-making. |
List of abbreviations
- CIG
- Canadian Immunization Guide
- CHMS
- Canadian Health Measures Survey
- CNDSS
- Canadian Notifiable Disease Surveillance System
- CSR
- Clinical Study Report
- HA
- Hepatitis A
- HB
- Hepatitis B
- HMD
- Hospital Morbidity Database
- HV
- Hexavalent Vaccine
- HWG
- Hepatitis Working Group
- Ig
- Human immune globulin
- IM
- Intramuscular
- GMC
- Geometric mean antibody concentration
- GMT
- Geometric mean titres
- mIU/ml
- milli-International Units/milliliter
- NESP
- National Enteric Surveillance Program
- NACI
- National Advisory Committee for Immunization
- RCT
- Randomized Controlled Trial
- S/D
- Solvent-detergent
Acknowledgments
(Alphabetical Order)
NACI Members: Dr. I. Gemmill (Chair), Dr. C. Quach (Vice-Chair), Dr. N. Dayneka, Dr. S. Deeks, Dr. B. Henry, Ms. S. Marchant-Short, Dr. M. Salvadori, Dr. N. Sicard, Dr. W. Vaudry, Dr. D. Vinh, Dr. R. Warrington.
Former NACI Members: Dr. D. Kumar, Dr. B. Seifert.
Liaison Representatives: Dr. J. Blake (Society of Obstetricians and Gynaecologists of Canada), Dr. J. Brophy (Canadian Association for Immunization Research and Evaluation [CAIRE]), Dr. A. Cohn (Centers for Disease Control and Prevention, United States), Dr. J. Emili (College of Family Physicians of Canada), Dr. M. Lavoie (Council of Chief Medical Officers of Health), Dr. C. Mah (Canadian Public Health Association), Dr. D. Moore (Canadian Paediatric Society), Dr. A. Pham-Huy (Association of Medical Microbiology and Infectious Disease [AMMI] Canada), Ms. E. Sartison (Canadian Immunization Committee).
Former Liaison Representatives: Dr. A. Mawle (Centers for Disease Control and Prevention, United States).
Ex-Officio Representatives: Dr. (LCdr) K. Barnes (National Defence and the Canadian Armed Forces), Ms. G. Charos (Centre for Immunization and Respiratory Infectious Diseases [CIRID], Public Health Agency of Canada [PHAC]), Dr. G. Coleman (Biologics and Genetic Therapies Directorate [BGTD], Health Canada [HC]), Dr. J. Gallivan (Marketed Health Products Directorate [MHPD], HC), Ms. J. Pennock (CIRID, PHAC), Dr. T. Wong (First Nations and Inuit Health Branch [FNIHB], HC).
Former Ex-Officio Representatives: Dr. J. Brooks (CIRID, PHAC), Dr. (LCol) P. Eagan (National Defence and the Canadian Armed Forces), Dr. D. Garcia (FNIHB, HC), Dr. B. Law (CIRID, PHAC), Ms. M. St-Laurent (CIRID, PHAC).
This statement was prepared by: Dr. O. Baclic (CIRID, PHAC), Dr. B. Henry (NACI), Ms. V. Morton (Centre for Food-Borne, Environmental and Zoonotic Infectious Diseases [CFEZID], PHAC) and approved by NACI.
NACI gratefully acknowledges the contribution of: Dr. M. Gale-Rowe (Centre for Communicable Diseases and Infection Control [CCDIC], PHAC), Dr. V. Gilca (Institut national de santé publique du Québec), Ms. P. Muchaal (CFEZID, PHAC), Ms. S. Totten (CCDIC, PHAC).
References
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