Summary of the National Advisory Committee on Immunization ( NACI ) Statement Update on the Recommended Use of Hepatitis A Vaccine

Background: The severity of hepatitis A (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. Immunization with HA vaccine is recommended for pre-exposure immunization of persons at increased risk of infection or severe HA, as well as within 14 days of HA exposure for: 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 where HA has occurred. Canada’s National Advisory Committee on Immunization (NACI) has previously recommended HA vaccination for persons one year of age and over. Objectives: To make recommendations for the use of HA vaccine in infants less than one year of age and to clarify recommendations for the post-exposure use of human immune globulin (Ig). Methods: The NACI Hepatitis Working Group (HWG) performed literature reviews and reviewed vaccine manufacturer provided data on the topic of HA post-exposure prophylaxis. All evidence was rated and reported in evidence tables. A knowledge synthesis was performed and NACI approved specific evidence-based recommendations, elucidating the rationale and relevant considerations. Results: No studies on the efficacy or effectiveness of HA-containing vaccines in children six to less than 12 months of age were identified through the literature search. Receipt of two doses of HA-containing vaccines was found to be safe and immunogenic in infants six to 12 months of age. Limited data were available regarding HA-containing vaccine immunogenicity in adults over the age of 40 years. Conclusion: There are now new NACI recommendations on HA vaccine and post-exposure use of Ig. Affiliations 1 National Advisory Committee on Immunization (NACI), Hepatitis Working Group Chair, Victoria, BC 2 Centre for Immunization and Respiratory Infectious Diseases, Public Health Agency of Canada, Ottawa, ON *Correspondence: naci-ccni@ phac-aspc.gc.ca


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.

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

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.

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.

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.

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
The severity of HA increases with age and can range from asymptomatic or a short and mild illness, to a severely disabling disease lasting several months. 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, with the majority of individuals developing anorexia, nausea, fatigue, fever and jaundice, usually lasting less than two months. Older persons, and individuals with chronic liver disease and immunocompromising conditions, have an increased risk of progressing to fulminant hepatic failure resulting in death. (1)(2)(3)(4)(5) Although HA is a reportable disease in all jurisdictions in Canada. At the national level, cases of HA are reported through the Canadian Notifiable Disease Surveillance System (CNDSS) (8) and the National Enteric Surveillance Program (NESP). (9,10) (3) There is currently no information available about HA seroprevalence in children less than 12 months of age.  Hepatitis A is the most common vaccine preventable disease in travellers. The risk of HA for susceptible travellers to developing countries is estimated to range from 0.1/1000 to 1/1,000 per month. The risk may be much higher for low-budget travellers, volunteer humanitarian workers and immigrants visiting friends and relatives in their homelands, who may be eating in less hygienic conditions. Additional information about disease incidence and distribution is available in the CIG's Hepatitis A vaccine chapter. (14) IV. VACCINES There is no change in vaccines currently authorized and available in Canada. Additional details about the types and contents of HA-containing vaccines available for use in Canada are provided in the CIG (http://www.phac-aspc.gc.ca/publicat/cig-gci/p04-hepa-eng.php). (14) 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.
In a randomized controlled trial conducted by Bell et al. (15) , immune responses of 82 infants vaccinated with HA vaccine at 6 and 12 months of age (Group 1) were compared to children who were immunized at 12 and 18 or 15 and 21 months of age (Groups 2 and 3, respectively). Seroresponse (proportion of children achieving seroprotection defined by study authors as titre ≥33 mIU/ml and GMC values) was analysed in relation to maternal HA antibody status. Following the receipt of the first vaccine dose, all children in all groups achieved and maintained seroprotection throughout the study period, except for 2 infants in Group 1 born to anti-HAVpositive mothers . While no statistically significant differences in GMC between the three groups were observed among children born to anti-HAV-negative mothers, children born to anti-HAV-positive mothers in Group 1 had significantly lower GMC than those in Groups 2 and 3 at all blood draws. A subgroup analysis showed higher GMC values following the second vaccine dose in Group 1 infants born to susceptible, compared to those born to seropositive mothers. These subgroup differences were not observed in Groups 2 and 3. When interpreting the results of the study, it is important to note the relatively small number of participants in Group 1, high seroprotective HA antibody titre threshold used by the authors, as well as high HA incidence and younger average maternal age in the geographic area where the study was conducted.
Long term immunogenicity results of the study by Bell et al. were subsequently reported by Sharapov et al, (16) who used a lower protective antibody cut-off level (titre ≥10 mIU/ml) than in the original study. Although a lower threshold for seroprotection resulted in all study participants achieving seroprotection one month after dose two, lower GMC values were noted at all time points for children in Group 1 compared to Groups 2 or 3, as well as for children born to anti-HAV-positive mothers compared to those born to anti-HAV-negative mothers. At 10 years, all but 7% of Group 1 children born to anti-HAV-negative mothers, 11% of Group 1 children born to anti-HAV-positive mothers, and 4% of Group 3 children born to anti-HAV-positive mothers maintained protective antibody levels.
Immune response of children born to anti-HAV-positive mothers was also assessed in a clinical trial by Lagos et al. (17) In the study, 91 seropositive children either received a first dose of HA vaccine at 6 months of age concomitantly with other routine infant vaccines, or two weeks following routine infant immunization; dose 2 was provided at 12 months of age. One month after dose one, seroprotection (defined as titre ≥20 mIU/ml) was achieved by all participants and both groups achieved more than a 22 fold increase in GMT values.
In a similar study, Stojanov et al. (18) randomized 619 infants to receive HA vaccine separately (months 7 and 13) or concomitantly (months 6 and 12) with other routine vaccines. Comparison of infants according to pre-vaccination HA antibody status (protective antibody titre defined as ≥10 mIU/ml) showed a pre-and post-booster response of similar magnitude, but significantly lower GMT values in initially seropositive infants. One month after dose 2, all infants achieved protective antibody levels, independent of initial HA antibody status.
Letson et al. (19) evaluated the immune response in 123 infants who were randomized according to maternal HA antibody status to receive HA vaccine at 2, 4, and 6 months of age (infants of both anti-HAV-positive and -negative mothers) or HA vaccine at 8 and 10 months of age (12 infants born to anti-HAV-positive mothers). In the latter group, at 15 months of age, no statistical differences in seroprotective levels (antibody titre >20 mIU/mL) were observed among infants who were seronegative (n=3) and those who were seropositive (n=9) at the time of vaccination (128 mIU/mL vs 72 mIU/mL, p=0.41).
Lopez et al. (20) conducted a study of 131 infants who received either three doses of HA vaccine at 2, 4, 6 months of age or one dose at 6 months of age, and a booster dose at 15-18 months of age. Seroprotective levels (defined as titre ≥20 mIU/ml) were achieved by all 30 participants who received the initial vaccine at 6 months of age, at one month following both primary and booster immunization, independent of prior antibody status (10% were seronegative at the time of enrolment). A 34-fold increase in pre-and post-booster GMC values was also observed among these study participants.
Usonis et al. (21) measured immune responses of 60 children following the receipt of the first dose of HA vaccine at either 5 to 10 months of age or 4 to 7 years of age, with a booster provided 12 months later. Half of the 26 infants who received a booster dose were seronegative (seroprotection defined as antibody titre ≥20 mIU/ml) prior to primary immunization. All infants achieved and maintained seroprotective antibody titers for the duration of the study, independent of the presence of maternal antibodies, with no statistically significant differences in antibody levels between the groups at month 12. Although the increase in GMT values following booster immunization was approximately four-fold higher in infants without maternal antibodies than in infants with maternal antibodies at baseline, all infants achieved more than fifty-fold higher antibody levels than those considered to be protective by the study authors.
In a study of 1084 children, Nolan et al. (22) compared immune responses of 218 children allocated to receive 2 doses of HA vaccine, starting at 11 to 13 months of age to children receiving the first dose of HA vaccine at 15 to 18 or 23 to 25 months of age. All children in all age groups reached seroprotective levels (defined as titre ≥15 mIU/ml) one month after dose 2. Seroresponse based on GMC values was found by authors to be equivalent between vaccine responders in the 11 to 13 and 23 to 25 month age groups.
There are limited data regarding HA vaccine immunogenicity in adults over the age of 40 years. (23)(24)(25) In a study by Briem et al (25) , immune responses were compared between 200 adults 20-39 years of age (Group 1) and 40 to 62 years of age (Group II). Although 15 days post vaccination, Group 1 achieved higher seroresponse rates than Group 2 (90% vs. 77%), at month 1 post-vaccination a seropositivity (titre ≥20 mIU/ml) rate of 97% was observed in both groups. Another study by D'Acremont et al. (23) that compared immune responses among 53 adults 18-45 years of age with 16 adults 50-60 years of age found higher seropositivity (titre ≥20 mIU/ml) in the younger age group (100% vs. 70%). In a study by Scheifele et al. (24) in which 57 adults 40-61 years of age were provided with a pediatric dose of HA vaccine (HAVRIX ® pediatric), seroprotection (titre ≥20 mIU/ml) was achieved by 89% of study participants one month following initial immunization and all participants one month after the receipt of the second dose.
Three studies (26)(27)(28) assessing the immunogenicity of HA vaccine in individuals with chronic liver disease were reviewed by the HWG. In a study conducted by Keeffe et al. (26) , immune response was compared between healthy adults and adults with chronic liver disease. Although the extent of liver damage in study participants did correlate to vaccine response, GMC values and seroconversion rates (titre ≥33 mIU/ml) after the first dose of HA vaccine were found to be statistically lower in adults with chronic liver disease. Similarly, in a study of 22 adult patients with liver failure and liver transplants conducted by Dumont et al (27) , seroconversion rates of 0% and 50% respectively, were much lower than those historically observed in healthy individuals.
In another non-randomized control study conducted by Fereirra et al. (28) , statistically lower seroconversion rates (p<0.05) were observed in children 1 to 16 years of age with chronic liver failure (76%), compared to healthy, age matched, children (94%).
It should be noted that, although immunity to HAV, by convention, has been established as IgG anti-HAV antibody titre above 10-20 mIU/ml (depending on the immunoassay used), the absolute lower limit of protective antibody level has not been determined. (2) It is also important to note that antibody levels induced by immunization have generally been observed to be lower in comparison to those induced by natural infection. (15,16,19) Available studies have primarily measured immune responses in children born to mothers who acquired antibodies through natural infection with HAV. Therefore, the ability to extrapolate the findings from these studies to children born to immunized anti-HAV positive mothers is limited.
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 HAcontaining 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 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. 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 caseby-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. 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.

HA vaccine
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.   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. 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. 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).  (3): 258-61. (28) months 0 and 6 Table 6. Levels of Evidence Based on Research Design 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.

Table 7. Quality (internal validity) Rating of Evidence
Good A study (including meta-analyses or systematic reviews) that meets all design-specific criteria* 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 criterion* but has no known "fatal flaw".

Poor
A study (including meta-analyses or systematic reviews) that has at least one designspecific* "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.

Table 8. NACI Recommendation for Immunization --Grades
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.