Adverse Events Following Immunization With Combined vs Concurrent Monovalent Hepatitis A and Typhoid Vaccines in Children

Abstract

Combined hepatitis A and typhoid vaccine is available in Australia, but licensed for use from age 16 years; however it is used “off-label” in children. The combined vaccine is well tolerated in children aged 2–16 years and the risk of adverse events is similar to those receiving concurrent monovalent vaccines.

Since 2006, a combined hepatitis A and typhoid vaccine has been available in Australia (Vivaxim, Sanofi-Aventis), but it has only been licensed for use for those aged ≥16 years [1]. In adults, a combined hepatitis A and typhoid vaccine has been widely used in many countries and found to be well tolerated and safe, with side effects and immunogenicity similar to those for the monovalent hepatitis A (eg, Avaxim 160, Sanofi-Aventis) and typhoid (eg, Typhim Vi, Sanofi-Aventis) vaccines.

The monovalent hepatitis A and typhoid vaccines are licensed for use in children aged ≥2 years, and both have been shown to be safe, with good immunogenic properties [2, 3]. These monovalent vaccines contain the same components and are have the same dosage as the combined vaccine [1]. In Australia, the combined vaccine has been frequently used in children aged 2–16 years “off label,” likely due to the preference for a single injection. To date, the only published study on adverse events following immunization (AEFIs) for Vivaxim in children aged 2–16 years found that it was safe and well tolerated [4]. A major limitation of that study was the lack of a control group (ie, children who received concurrent monovalent vaccines on the same day). Nevertheless, the study provided valuable information to support the use of Vivaxim in children [5].

In this study, we further investigated the safety and tolerability of Vivaxim in children by directly comparing AEFIs in children aged 2–16 years who received Vivaxim vs concurrent monovalent vaccines in Australian primary care and travel medicine clinics.

METHODS

Ethical approval for this study was obtained through the Australian National University Human Research Ethics Committee (protocol: 2018/792). SmartVax’s ethics approval was obtained through the Royal Australian College of General Practitioners. All data were deidentified prior to analyses.

Children aged 2–16 years who received Vivaxim or concurrent monovalent hepatitis A (Avaxim, Havrix 1440, Havrix Junior, Vaqta adult, Vaqta paediatric) and typhoid (Typherix, Typhim Vi) vaccines between 16 April 2015 and 1 July 2019 at participating clinics in Australia that use SmartVax were included in the study [6]. Children who received another vaccine(s) on the same day were excluded from the analyses. In addition, children who received only the monovalent hepatitis A vaccine or the monovalent typhoid vaccine in a single encounter were excluded. SmartVax is an active monitoring system for AEFIs that is currently used in more than 320 general practice and travel medicine clinics across Australia. It uses short message service (SMS) to collect data from vaccine recipients and integrates this information with clinical data extracted from commercially available medical practice management software. SmartVax sends automated SMS messages to patients, parents, or guardians 3 to 5 days after vaccination to enquire about AEFIs. If an AEFI is reported through the SMS message, a link is sent to an online survey to ascertain the nature of the adverse event, including local (pain, swelling, rash) or systemic (tiredness/fatigue, fever, irritability, headache, sleep disturbance, vomiting, diarrhea, rigors, hypotonia, convulsions) reactions. General practices are automatically notified via their practice software if any of their patients report a medically attended AEFI.

Demographic characteristics were compared between those who received Vivaxim and monovalent vaccines. Age was categorized into 3 groups (2–5 years, 6–12 years, and 13–16 years) to approximately reflect preschool, primary school, and high school ages. The proportion of overall AEFIs, local and systemic reactions, and specific AEFIs reported in the Vivaxim and the monovalent vaccines groups were compared. Multivariable logistic regression models were built to estimate the odds of an AEFI with Vivaxim compared with monovalent vaccines after adjusting for difference in demographic characteristics. All tests were 2-tailed and a P value of <.05 was deemed statistically significant. All analyses were conducted using Stata MP, version 14 (StataCorp, College Station, TX).

RESULTS

A total of 13 921 children who received Vivaxim, monovalent hepatitis A vaccine, or monovalent typhoid vaccine were identified in the SmartVax database. Of these, 236 were aged <2 years and excluded from analyses. Of the 2302 children who received Vivaxim, 987 received another vaccine on the same day and were excluded. Of the 11 383 children who received monovalent hepatitis A vaccine or monovalent typhoid vaccine, 4912 were excluded because they either received only 1 of the vaccines (ie, hepatitis A or typhoid vaccine) or the monovalent vaccines in combination with another vaccine the same day. Therefore, 7786 children (1315 Vivaxim, 6471 concurrent monovalent vaccines) from 231 primary care and travel medicine clinics from all Australian 8 states and territories were included in the study (see the Supplementary Material S1).

Half of the children were female and the median age was 8 years (interquartile range [IQR], 5–13 years). There were differences in the demographic characteristics of the children who received Vivaxim and those who received concurrent monovalent vaccines; more females (55.5%) received Vivaxim, while slightly more males (51.1%) received concurrent monovalent vaccines. Children who received Vivaxim (14 years; IQR, 8–16 years) were older than those who received concurrent monovalent vaccines (8 years; IQR, 4–11 years; P < .001; Table 1).

Table 1.

Demographic Characteristics and Adverse Events Following Immunization by Type of Vaccine Received

Characteristic	Vivaxim, n = 1315	Concurrent Monovalent Hepatitis A and Typhoid Vaccines, n = 6471	P Value
Sexa
Female (%)	730 (55.5)	3151 (48.7)	<.001
Age group
2–5 years (%)	190 (14.5)	2267 (35.0)	<.001
6–12 years (%)	371 (28.2)	2977 (46.0)
13–16 years (%)	754 (57.3)	1227 (19.0)
Median age (interquartile range), y	14 (8–16)	8 (4–11)	<.001
Adverse event following immunization
Overall (%)	38 (2.9)	212 (3.3)	.469
Local reaction (%)	16 (1.2)	76 (1.2)	.897
Pain (%)	14 (1.1)	69 (1.1)	.996
Swelling (%)	7 (0.5)	26 (0.4)	.507
Rash (%)	1 (0.1)	4 (0.1)	.853
Systemic reaction (%)	14 (1.1)	73 (1.1)	.842
Tiredness/fatigue (%)	7 (0.5)	44 (0.7)	.545
Fever (%)	6 (0.5)	38 (0.6)	.564
Irritability (%)	4 (0.3)	21 (0.3)	.905
Headache (%)	3 (0.2)	20 (0.3)	.622
Sleep disturbance (%)	2 (0.2)	12 (0.2)	.795
Vomiting (%)	4 (0.3)	9 (0.1)	.181
Diarrhea (%)	1 (0.1)	5 (0.1)	.988
Rigors (%)	2 (0.2)	4 (0.1)	.282
Hypotonia (%)	1 (0.1)	2 (0.1)	.447
Convulsions (%)	0 (0)	0 (0)	NA
Other (%)	2 (0.2)	10 (0.2)	.984

^aSex information was not available for 15 children. NA, not applicable.

The proportion of children who reported an AEFI was comparable in both groups (2.9% Vivaxim, 3.3% concurrent monovalent vaccines; P = .469). A similar proportion of children reported local (1.2%) and systemic (1.1%) reactions in the Vivaxim and the concurrent monovalent vaccines groups. The most common local reactions in both groups were pain (1.1%) and swelling (0.4%), while tiredness/fatigue (0.7%) and fever (0.6%) were the most common systemic reactions reported. There was no difference in the proportion of children who reported specific AEFIs between those who received Vivaxim and monovalent vaccines (Table 1).

Sex and age (as a continuous variable and as age groups) of the children were examined as potential predictors for AEFIs and local and systemic reactions (see the Supplementary Material S2). After adjusting for sex and age group, the odds of an AEFI (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.66–1.39), local reaction (OR, 0.93; 95% CI, 0.52–1.66), and systemic reaction (OR, 0.90; 95% CI, 0.49–1.66) in children who received Vivaxim were similar to those who received the monovalent vaccines (Table 2). Age was not an interaction term (or effect modifier) for the association between the type of vaccine and AEFI and local and systemic reactions. This indicates that the risk of an AEFI and local and systemic reactions associated with the type of vaccine are not different across age groups.

Table 2.

Multivariable Logistic Regression Models for Independent Predictors of Adverse Events Following Immunization, Local Reactions, and Systemic Reactions

	Adverse Event Following Immunization, OR (95% CI)	Local Reaction, OR (95% CI)	Systemic Reaction, OR (95%CI)
Sex
Male (reference)	1	1	1
Female	1.20 (0.93–1.55)	1.03 (0.68–1.56)	0.85 (0.55–1.30)
Age categories
2–5 years (reference)	1	1	1
6–12 years	0.83 (0.63–1.11)	1.01 (0.61–1.66)	0.92 (0.56–1.52)
13–16 years	0.71 (0.50–1.02)	1.32 (0.75–2.30)	1.11 (0.63–1.98)
Vaccine
Concurrent monovalent vaccines (reference)	1	1	1
Vivaxim	0.96 (0.66–1.39)	0.93 (0.52–1.66)	0.90 (0.49–1.66)

Adverse events following immunization include local and systemic reactions. Local reactions include pain, swelling, and rash. Systemic reactions include tiredness/fatigue, fever, irritability, headache, sleep disturbance, vomiting, diarrhea, rigors, hypotonia, and convulsions.

Abbreviations: CI, confidence interval; OR, odds ratio.

DISCUSSION

Using a large dataset of patients collected through Australian primary care and travel medicine clinics, we confirm previous findings [4] that Vivaxim is safe and well tolerated in children, with less than 3% of children who received Vivaxim reporting an AEFI. When comparing Vivaxim with concurrent monovalent vaccines, the risk of an AEFI was similar in both groups. Vivaxim is a suitable alternative to the monovalent vaccines due to the similar safety profiles and costs in Australia (Vivaxim, approximately USD 85 Avaxim hepatitis A + Typhim Vi, approximately USD 70), with the advantage of a single injection with the former. Although the benefit of a single injection in children is hard to quantify, it is perceived by many parents as the preferable option, particularly when multiple other vaccines are recommended. In adults, the effectiveness of Vivaxim is comparable to that of concurrent monovalent vaccines [7–9]; this has not yet been confirmed in the pediatric population, but it is unlikely to be different as the active components in Vivaxim [1] and the monovalent vaccines are the same.

The current study adds to the evidence on vaccination options for children who travel to hepatitis A and typhoid endemic areas; however, the findings have to be interpreted in light of the limitations of the study. The response rate in SmartVax ranges between 70% and 74% [10]; parents/guardians of children who experienced an AEFI might be more likely to respond to SmartVax messages and report the adverse reaction compared with those who did not experience an AEFI. This reporting bias could lead to an overestimate of the proportion of children who experience an AEFI, but it is unlikely that the response rate would be associated with the type of vaccine received. The severity of the AEFI (eg, required in-hospital care), the follow-up information after an adverse event, and whether the monovalent vaccines were administered in the same arm or different arms were not available in the dataset. Finally, the indication and designation of symptoms relied on self-assessment by the children and/or their parents/guardians.

In conclusion, Vivaxim was well tolerated in children aged 2–16 years. We did not find any evidence of increased risk of overall AEFIs, local reaction, or systemic reactions with Vivaxim compared with concurrent monovalent vaccines. These findings are reassuring, and we encourage healthcare providers to discuss Vivaxim as an option with parents/guardians while advising them that it is “off-label.” Further research needs to be conducted to investigate the immunogenicity of Vivaxim in children against the monovalent vaccines. Combined vaccines have been shown to have immunogenicity that is similar to that of monovalent vaccine, but the former may require larger amount of antigen to achieve the same results (eg, measles, mumps, rubella, and varicella vaccine vs measles, mumps, and rubella plus varicella vaccine) [11]. In addition, future studies need to assess any possible delayed adverse events associated with Vivaxim in these age groups.

Notes

Acknowledgments. We thank the doctors, nurses, and staff who supported the SmartVax program in the collection of data. We also thank the children and parents for their cooperation with the collection of data.

Author contribution. Conception and design of the study: P. D., D. M., and C. L. L. Collection and assembly of the dataset: A. L. Analysis of the dataset and interpretation of results: L. F. K., R. A., and C. L. L. Manuscript writing: all authors. Final approval of the manuscript: all authors.

Financial support. C. L. L. and L. F. K. were supported by Australian National Health and Medical Research Council Early Career fellowships (APP1109035 and APP1158469).

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.