Safety and immunogenicity of VAQTA® in children 12-to-23 months of age with and without administration of other US pediatric vaccines

ABSTRACT

Safety and immunogenicity data from 5 clinical trials conducted in the US in children 12-to-23 months old where HAVi was administered alone or concomitantly with other pediatric vaccines (M-M-R®II, Varivax®, TRIPEDIA®, Prevnar®, ProQuad®, PedvaxHIB®, and INFANRIX®) were combined. Among 4,374 participants receiving ≥ 1 dose of HAVi, 4,222 (97%) had safety follow-up and the proportions reporting adverse events (AE) were comparable when administered alone (69.4%) or concomitantly with other pediatric vaccines (71.1%). The most common solicited injection-site AEs were pain/tenderness (Postdose 1: 25.8%; Postdose 2: 26.1%) and redness (Postdose 1: 13.6%; Postdose 2: 15.1%). The most common vaccine-related systemic AEs were fever (≥ 100.4ºF, 12.2%) and irritability (8.1%). Serious AEs (SAEs) were observed at a rate of 0.4%; 0.1% were considered vaccine-related. No deaths were reported within 14 days following a dose of HAVi. These integrated analyses also showed that protective antibody concentrations were elicited in 100% of toddlers after two doses and 92% after a single dose, regardless of whether HAVi was given concomitantly with other vaccines or alone. These results demonstrate that HAVi was well-tolerated whether given alone or concomitantly with other vaccines, with a low incidence of vaccine-related SAEs. HAVi was immunogenic in this age group regardless of whether administered with or without other pediatric vaccines and whether 1 or 2 doses were administered. HAVi did not impact the immune response to other vaccines. These data continue to support the routine use of HAVi with other pediatric vaccines in children ≥ 12 months of age.

Introduction

VAQTA® (Hepatitis A Vaccine, Inactivated [HAVi], absorbed; Merck & Co., Inc., Kenilworth, NJ, USA) is licensed in the United States (US) and recommended by the Advisory Committee on Immunization Practices (ACIP) for vaccination against hepatitis A in persons ≥ 12 months of age. The standard dose is 25 U/0.5 mL for persons 12 months through 18 years of age and 50 U/1.0 mL for persons ≥ 19 years of age.¹ Two doses of the vaccine, administered 6-to-18 months apart, are recommended.² Clinical trials conducted worldwide have demonstrated that HAVi vaccine is efficacious, immunogenic, and well-tolerated.^3-16

In the US, hepatitis A was the most frequently reported type of hepatitis during the 1980s and 1990s, with an average of 26,000 cases reported per year.¹⁷ However, the actual number of infections is known to have been several times higher, estimated at 270,000 annually, after correction of underreporting and asymptomatic disease.¹⁸ The American Committee on Immunization Practices (ACIP), American Academy of Family Physicians, and American Academy of Pediatrics recommend that children between the ages of 12-to-23 months receive hepatitis A vaccines as well as vaccines containing antigens for hepatitis B, diphtheria, tetanus, pertussis, Haemophilus influenzae type B (Hib), poliovirus, pneumococcus, measles, mumps, rubella, and varicella.¹⁹ HAV administered to children 12-to-23 months of age would likely be given concomitantly with one or more of these other recommended vaccines.

Considering the large number of other pediatric vaccines administered routinely between 12-to-23 months of age,¹⁹ concomitant use studies are important to provide assurance that multiple vaccines may be administered at the same health encounter, without causing either safety (e.g., increased reactogenicity) or immunogenicity issues. Immune interference among co-administered polysaccharide-protein conjugate vaccines has been previously reported.²⁰

As of June 2017, over 128 million doses of HAVi were distributed worldwide. The product was first approved in 1996 in the US for persons ≥ 2 years of age and subsequently approved for use in children ≥ 12 months of age. The purpose of this paper is to describe the safety and immunogenicity of HAVi administered across 5 clinical studies to children 12-to-23 months of age conducted in the US.

Results

Participants accounting and demographics

Participant characteristics (gender and age) at study entry were comparable between these vaccination group categories (Table 1). Across the 5 clinical trials, 4,374 participants received at least 1 dose of HAVi. Of the 4,374 participants vaccinated, 1,456 (33%) received HAVi concomitantly with other vaccines. Supplemental Table 1 presents the number of participants who were vaccinated, completed, or discontinued in Studies 1 and 2 (non-randomized) and Studies 3, 4, and 5 (individually randomized). A total of 3,249 (74%) children received 2 doses.

Table 1.

Participant characteristics by vaccination group (Studies 1–5 combined).

	Recipients of HAVi Alone		Recipients of HAVi Concomitantly with Other Vaccines		All Recipients of HAVi
	N	%	n	%	N	%
Gender
Male	1503	51.5%	763	52.4%	2266	51.8%
Female	1415	48.5%	693	47.6%	2108	48.2%
Age at Study Entry (Months)
Mean (SD)	13.4 (1.74)		12.9 (1.29)		13.2 (1.63)
Range	11 to 23		11 to 17		11 to 23
Race
Asian	49	1.7%	14	1.0%	63	1.4%
Black	351	12.0%	186	12.8%	537	12.3%
Hispanic American	366	12.5%	322	22.1%	688	15.7%
Native American	15	0.5%	33	2.3%	48	1.1%
White	1995	68.4%	834	57.3%	2829	64.7%
Other	142	4.9%	67	4.6%	209	4.8%
Total	2918	67%	1456	33%	4376	100%

N = number of participants vaccinated with at least one dose of HAVi

n = number of participants in the indicated category

SD = standard deviation

Adverse events (aes)

Out of 4,374 vaccinated participants, 4,222 (97%) had safety follow-up available. Of the 4,222 participants with safety follow-up, 2,954 (70.0%) reported ≥ 1 adverse events (AEs) within 14 days following a dose of HAVi (Table 2). Of the 2,954 participants who reported an AE, 1,684 (39.9%) reported injection-site AEs, 2,352 (55.7%) reported systemic AEs, 1,668 (39.9%) reported vaccine-related injection-site AEs, and 1,023 (24.2%) reported vaccine-related systemic AEs. No deaths were reported within 14 days following a dose of HAVi. The most common reported systemic AEs, days 1 to 14 following any vaccination, were fever (19.9%) and irritability (10.6%) in all recipients of HAVi (Supplemental Table 2). Overall, serious AEs (SAEs) incidence rates (≥ 1%) were similar whether HAVi was given concomitantly or alone.

Table 2.

Overall clinical adverse experience by vaccination group: days 1 to 14 following any vaccination (Studies 1–5 combined).

	Recipients of HAVi Alone		Recipients of HAVi Concomitantly with Other Vaccines		All Recipients of HAVi
	N	%	n	%	n	%
Number of participants	2918		1456		4374
Participants with follow-up	2828		1394		4222
With one or more AEs	1963	69.4%	991	71.1%	2954	70.0%
Injection-site AEs	1189	42.0%	495	35.5%	1684	39.9%
Systemic AEs	1513	53.5%	839	60.2%	2352	55.7%
With vaccine-related AEs1	1450	51.3%	728	52.2%	2178	51.6%
Injection-site AEs	1179	41.7%	489	35.1%	1668	39.5%
Systemic AEs	586	20.7%	437	31.3%	1023	24.2%
With serious AEs	10	0.4%	5	0.4%	15	0.4%
With serious vaccine-related AEs	1	0.0%	2	0.1%	3	0.1%
Who died	0	0.0%	0	0.0%	0	0.0%
Discontinued due to an AE	1	0.0%	1	0.1%	2	0.0%
Due to a vaccine-related AE	0	0.0%	1	0.1%	1	0.0%
Due to a serious AE	1	0.0%	0	0.0%	1	0.0%
Due to a serious vaccine-related AE	0	0.0%	0	0.0%	0	0.0%

¹Determined by the investigator to be possibly, probably or definitely related to the vaccine

Percentages are calculated based on the number of participants with follow-up after any dose of HAVi

Only injection-site adverse events at the site of HAVi are included in this table

N = number of participants vaccinated with at least one dose of HAVi in each group

n = Number of participants counting in each adverse event category

For all recipients of HAVi, the most frequently reported injection-site AE was pain/tenderness (37.3%) and the most common unsolicited injection-site AE was bruising (1.8%) (Table 3). The incidence of local (Table 3) and general (Supplemental Table 2) symptoms did not increase, with the exception of fever, when HAVi was co-administered compared with when other vaccines were administered alone. Among recipients of HAVi administered concomitantly with other vaccine, 27% reported fever as compared to 16.4% among those receiving HAVi alone.

Table 3.

Injection site adverse events by vaccination group: days 1 to 5 following any vaccination (Studies 3–5 combined).

	Recipients of HAVi Alone		Recipients of HAVi Concomitantly with Other Vaccines		All Recipients of HAVi
	N	% (95% CI)	n	% (95% CI)	n	% (95% CI)
Number of participants	2677		991		3668
Participants with follow-up	2592		947		3539
With one or more Injection-site AEs	1144	44.1% (42.2, 46.1)	405	42.8% (39.6, 46.0)	1549	43.8% (42.1, 45.4)
Solicited Events
Pain/Tenderness	975	37.6% (35.7, 39.5)	344	36.3% (33.3, 39.5)	1319	37.3% (35.7, 38.9)
Redness (Erythema)	565	21.8% (20.2, 23.4)	195	20.6% (18.1, 23.3)	760	21.5% (20.1, 22.9)
Swelling	333	12.8% (11.6, 14.2)	139	14.7% (12.5, 17.1)	472	13.3% (12.2, 14.5)
Unsolicited Events
Injection-site Bruising	46	1.8% (1.3, 2.4)	16	1.7% (1.0, 2.7)	62	1.8% (1.3, 2.2)
Injection-site Hematoma	28	1.1% (0.7, 1.6)	8	0.8% (0.4, 1.7)	36	1.0% (0.7, 1.4)

*Data collected using a validated vaccine report card, including specific solicited events

Percentages are calculated based on the number of participants with follow-up after any dose of HAVi

Only injection-site AEs at the site of HAVi are included in this table

N = number of participants vaccinated with at least one dose of HAVi in each group

n = number of participants counting in each adverse event category.

The most commonly reported vaccine-related systemic AEs, were fever (12.2%) and irritability (8.1%) (Table 4). Overall, the percentage of participants reporting vaccine-related systemic AEs was generally lower in the recipients of HAVi alone. Three (3) vaccine-related SAEs were reported within 14 days postvaccination: febrile seizure, 9 days postdose 1 (Study 2); dehydration and gastroenteritis, 13 days postdose 2 (Study 4); and febrile seizure, 9 days postdose 1 (Study 4). The two febrile seizures occurred in participants that received HAVi concomitantly with MMRV vaccine. One SAE of cerebral vascular accident that resulted in death was reported in Study 3 in a 21-month-old male participant (with a medical-surgical history of plagiocephaly, spastic quadriparesis, failure to thrive, microcephalus, cerebral palsy, developmental delay, and difficulty feeding from severe neuromuscular disabilities) at 75 days postdose 2 of HAVi; this was assessed by the investigator as definitely not related to study vaccines.

Table 4.

Vaccine-related systemic adverse events by vaccination group: days 1 to 14 following any vaccination (Studies 1–5 combined).

	Recipients of HAVi Alone		Recipients of HAVi Concomitantly with Other Vaccines		All Recipients of HAVi
	N	% (95% CI)	n	% (95% CI)	n	% (95% CI)
Number of participants	2918		1456		4374
Participants with follow-up	2828		1394		4222
With One Or More Systemic AEs	586	20.7% (19.2, 22.3)	437	31.3% (28.9, 33.9)	1023	24.2% (22.9, 25.6)
Fever	252	8.9% (7.9, 10.0)	265	19.0% (17.0, 21.2)	517	12.2% (11.3, 13.3)
Irritability	216	7.6% (6.7, 8.7)	125	9.0% (7.5, 10.6)	341	8.1% (7.3, 8.9)
Diarrhea	65	2.3% (1.8, 2.9)	28	2.0% (1.3, 2.9)	93	2.2% (1.8, 2.7)
Vomiting	31	1.1% (0.7, 1.6)	14	1.0% (0.6, 1.7)	45	1.1% (0.8, 1.4)
Rhinorrhea	22	0.8% (0.5, 1.2)	23	1.6% (1.0, 2.5)	45	1.1% (0.8, 1.4)
Upper Respiratory Tract Infection	27	1.0% (0.6, 1.4)	14	1.0% (0.6, 1.7)	41	1.0% (0.7, 1.3)
Cough	16	0.6% (0.3, 0.9)	20	1.4% (0.9, 2.2)	36	0.9% (0.6, 1.2)
Rash	13	0.5% (0.2, 0.8)	16	1.1% (0.7, 1.9)	29	0.7% (0.5, 1.0)
Rash Morbilliform	0	0.0% (0.0, 0.1)	25	1.8% (1.2, 2.6)	25	0.6% (0.4, 0.9)

^† Determined by the investigator to be possibly, probably, or definitely related to the vaccine

Percentages are calculated based on the number of participants with follow-up after any dose of HAVi

N = number of participants vaccinated with at least one dose of HAVi in each group

n = number of participants counting in each adverse event category

Two participants discontinued due to an AE. One participant in Study 2 discontinued the study due to the clinical AEs of crying, rhinorrhea and fever following vaccination with HAVi, which was considered to be possibly related to vaccine. In Study 4, one participant (HAVi alone) discontinued the study due to a SAE (gastrointestinal hemorrhage); the investigator considered the event as definitely not related to study vaccination.

The percentage of participants who reported a maximum body temperature ≥ 100.4ºF (≥ 38.0ºC) to < 102.2°F (< 39.0°C) oral equivalent 1-to-5 days following any vaccination was slightly higher in participants who received HAVi concomitantly with other vaccines (18.6%) compared to participants who received it alone (15.6%) (Table 5). The percentage of participants who reported a maximum body temperature ≥ 102.2ºF (≥ 39.0ºC) oral equivalent appeared comparable in both vaccinated groups (4.2% and 4.8%, respectively).

Table 5.

Summary of body temperatures using brighton collaboration temperature categories by vaccination group: days 1 to 5 following any vaccination (Studies 1–5 combined).

	Recipients of HAVi Alone		Recipients of HAVi Concomitantly with Other Vaccines		All Recipients of HAVi
	(N = 2918)		(N = 1456)		(N = 4374)
	N	% (95% CI)	n	% (95% CI)	n	% (95% CI)
Number of Participants	2918		1456		4374
Participants with follow-up	2762		1350		4112
Maximum Temperature, Oral Equivalent
< 100.4°F [< 38.0°C] or Normal1	2330	84.4% (83.0, 85.7)	1099	81.4% (79.2, 83.4)	3429	83.4% (82.2, 84.5)
≥ 100.4°F [> 38.0°C] or Febrile1	432	15.6% (14.3, 17.0)	251	18.6% (16.6, 20.8)	683	16.6% (15.5, 17.8)
< 102.2°F [< 39.0°C] or Normal1	2645	95.8% (94.9, 96.5)	1285	95.2% (93.9, 96.3)	3930	95.6% (94.9, 96.2)
≥ 102.2°F [> 39.0°C] or Febrile1	117	4.2% (3.5, 5.1)	65	4.8% (3.7, 6.1)	182	4.4% (3.8, 5.1)
Abnormal1	4	0.1% (0.0, 0.4)	4	0.3% (0.1, 0.8)	8	0.2% (0.1, 0.4)

¹ Qualitative temperatures (Normal or Abnormal/Febrile) were permitted in Protocols 043 and 057 (Studies 1 and 2)

Percentages are calculated based on the number of participants with follow-up after any dose of HAVi

All temperatures have been converted to oral equivalent by adding 1 °F to axillary temperatures or subtracting 1 °F from rectal temperatures

N = number of participants vaccinated with any dose of HAVi in each group

n = number of participants counting in each temperature category

Immunogenicity

Of the 1,022 initially seronegative participants who received 2 doses of HAVi either separately from or concomitantly with other vaccines, 99.9% achieved a titer ≥ 10 mIU/mL (95% confidence interval [CI]: 99.5%, 100%); the geometric mean titer (GMT) was 5392.1 mIU/mL (95% CI: 4996.5, 5819.0, 4 weeks after dose 2) (Table 6). The seroconversion rates and GMTs were comparable whether both doses of HAVi were given alone compared with when at least one dose of HAVi was administered with another vaccine (overlapping 95% CIs).

Table 6.

Summary of hepatitis A antibody response postdose 2 of HAVi in initially seronegative participants (Studies 2, 4 and 5 combined).

			Seroconversion Rate (SCR)		GMT
Treatment Group Category	N	n	Response	95% CI	Response	95% CI
Both Doses of HAVi Given Concomitantly with Other Vaccines	486	255	100% (255/255)	(98.6%, 100.0%)	5592.5	(4754.1, 6578.8)
Dose 1 of HAVi Given Concomitantly and Dose 2 Given Alone	467	269	100% (269/269)	(98.6%, 100.0%)	4411.2	(3840.9, 5066.1)
Dose 1 of HAVi Given Alone and Dose 2 Given Concomitantly with Other Pediatric Vaccines	156	86	100% (86/86)	(95.8%, 100.0%)	5890.4	(4658.7, 7447.7)
Both Doses of HAVi Given Alone	778	412	99.8% (411/412)	(98.7%, 100.0%)	5900.1	(5218.9, 6670.2)
All Recipients of Two Doses of HAVi	1887	1022	99.9% (1021/1022)	(99.5%, 100.0%)	5392.1	(4996.5, 5819.0)

Seroconversion defined as baseline titer < 10 mIU/mL and Postdose 1 titer ≥ 10 mIU/mL by either the modified HAVAB assay or the Quantitative HAVK PLUS EIA.

N = number of participants enrolled who received at least one injection of study vaccine., n = number of initially seronegative participants contributing to the Per-Protocol analysis population, CI = confidence interval, GMT = Geometric Mean Titer

Study 2 was the only immunogenicity study that evaluated seroconversion rates after a single dose. Across all subjects with serology data, seroconversion rates 6 weeks after 1 dose varied by group but remained above 92%, regardless of whether the dose was given concomitantly with other vaccines or not. Among the 471 initially seronegative subjects who received a single dose, 95.5% (95% CI: 93.3%, 97.2%) achieved a titer ≥ 10 mIU/mL and a GMT of 48.1 mIU/mL (95% CI: 44.4, 52.2) was observed.

Study 2 and Study 5 evaluated the concomitant administration of HAVi with DTaP vaccine. In both studies the statistical criteria for similarity were met for diphtheria and tetanus. Study 5 was designed and powered to compare pertussis responses with or without concomitant HAVi and demonstrated non-inferiority in the GMT for antibody to pertussis PT, filamentous hemagglutinin (FHA) and pertactin (PRN) (Supplemental Table 3). The antibody responses for H. influenzae B (Hib) in Study 5 at Day 1 and Week 4 post-vaccination, among participants who received HAVi concomitantly or non-concomitantly with DTaP vaccine & Hib vaccine or HAVi concomitantly or non-concomitantly with Hib vaccine, are shown in Supplemental Table 4. The primary endpoint for PRP was the antibody response rate to PRP (defined as the proportion of participants with anti-PRP titers > 1.0 mcg/mL) 4 weeks postvaccination with Hib vaccine. The proportion of participants with anti-PRP titers > 1.0 mcg/mL at Week 4 postvaccination of Hib vaccine was comparable across the 4 treatment groups regardless of Hib vaccination history: 98.1%, 97.0%, 97.3% and 97.2% for Groups 1 through 4, respectively.

Discussion

Our results indicated that among > 4,300 enrolled participants (12-to-23 months of age) across the 5 clinical studies conducted in the US, HAVi was well tolerated and elicited protective immunity, whether given alone or concomitantly with other routinely administered pediatric vaccines.

These integrated safety results, in toddlers, are consistent with individual trial results in the same age group as well as with the safety data collected from other clinical trials and post-licensure studies over the last two decades.^3-16 HAVi has been shown to be generally well-tolerated in a number of clinical trials with the majority of reported AEs being mild and consisting of either injection-site related events (e.g. erythema, swelling, pain, tenderness) or systemic but not serious events (e.g. fever, irritability, diarrhea, vomiting, nausea, and headache).^3-16

These integrated immunogenicity analyses also showed that HAVi protective antibody concentrations were elicited in 100% of participants after two doses and 92% after a single dose regardless of whether HAVi was given concomitantly or not. These analyses also showed that HAVi does not affect the safety and immunogenicity profile of other vaccines, when given concomitantly. These immunogenicity results are also consistent with results obtained from other clinical trials and post-licensure studies conducted over the last two decades.^3-15 The current integrated analysis adds to what is known about HAVi by showing that the seroconversion rate is 100% after two doses and the safety profile is benign when HAVi is given with other commonly administered vaccines in a large number (> 4,000) of vaccinees between 12 and 23 months of age.

Integrated safety analyses have limitations. Firstly, formal statistical comparisons between the two groups (HAVi alone and HAVi given concomitantly with other vaccines) were not planned due to the non-randomized nature of the groups to be compared. Secondly, some trials did not use the same collection methods (e.g. ascertainment, frequency and/or reporting of protocol-specific AE injection-site reactions). Thirdly there were group size imbalances (data not shown). Although integrated safety analyses can be affected by methodological limitations, as described above, the incidences of systemic and injection-site AEs, and most common AEs, following HAVi were within the ranges for other licensed hepatitis A vaccines.^7,21-23

Since its introduction in the US in 2006, HAVi has contributed to an all-time low for hepatitis A disease burden in the US.²⁴ Such impact has been possible because HAVi is highly immunogenic and has durable and high protective efficacy against clinical hepatitis A. The clinical efficacy of HAVi was demonstrated, among 1,000 children 2–16 years of age, in a randomized placebo controlled pivotal study. A single dose of HAVi showed 100% protective efficacy (p < 0.001).³ The estimates of duration of protection after 2 doses suggest that HAVi will provide protection for many years (at least 25 years), first through the persistence of antibody and further through an anamnestic response based on long-term immune memory.²⁴ Despite its remarkable public heath impact, there still remains a substantial hepatitis A burden in the US given that hepatitis A vaccine uptake in 19–35 month old children is ~ 63%, well below the coverage rates of other pediatric and adolescent vaccines.²⁵

Demonstrating safety and lack of immune interference among co-administered vaccines in formal concomitant use studies of the type summarized in the current integrated analysis represent the first steps towards gaining acceptance of immunization regimens with multiple vaccines administered at single visits. Increasing numbers of parents are requesting to delay or “spread out” the recommended vaccination schedule, with the consequence of increasing periods of risk for vaccine-preventable diseases.²⁶ Despite lack of scientific evidence, parental concerns over overloading the immune system or the safety of multiple vaccines administered at 1 office visit persist.²⁷ The types of data summarized in the current study add to the large body of evidence that multiple licensed vaccines may be safely co-administered.

In summary, administration of 1 or 2 doses of HAVi was well tolerated and highly immunogenic in over 4,300 children 12-to-23 months of age whether given alone or concomitantly with other vaccines in US. These data support the continued routine use of HAV concomitantly with other ACIP recommended vaccines in children starting at 12 months of age. Since increasing pediatric hepatitis A vaccine coverage, in the US, has been shown to be cost saving from both a societal and payer perspective,^18,28 continued efforts to increase hepatitis A vaccine uptake are warranted.

Methods

Study design

Data from 5 open-label, clinical studies (Protocols 043, 057, 066 [NCT00326183], 067 [NCT00312858], and 068 [NCT00289913], subsequently referred to as Studies 1, 2, 3, 4 and 5) of HAVi among children 12-to-23 months of age, completed between 1997 and 2010, were included in this summary.^3,29-31 Participants either received HAVi alone or concomitantly with other pediatric vaccines. Two doses (25U/0.5 mL) of HAVi were given intramuscularly at least 6 months apart. Where possible, safety data were integrated across the 5 studies conducted in this population. However, due to differences in safety data collection methods (e.g. studies 1 and 2 investigators were instructed to only report injection-site AEs that were “clinically meaningful”), it was only appropriate to integrate data across all studies for some safety parameters. Injection-site AEs from the more recent studies (Studies 3, 4 and 5) with similar safety data collection methodology were integrated, while data from the first 2 studies (Studies 1 and 2) are presented separately. Studies 1 and 3 collected safety data only; immunogenicity was not assessed. Studies 2, 4 and 5 evaluated both the safety and immunogenicity of HAVi given concomitantly and non-concomitantly with other vaccines.

The age range for enrollment varied across the 5 studies: 12 months to 16 years in Study 1; 12-to-24 months in Studies 2, 3 and 4, and 15-to-24 months in Study 5. In all studies, participants were to have no clinical history of previous hepatitis A infection, no allergy to any vaccine component, and no prior receipt of any hepatitis A vaccine. In accordance with principles of Good Clinical Practice, parents/guardians provided written informed consent before they were enrolled.

Parents/guardians were requested to report fever, injection-site AEs, and systemic AEs through the use of a Vaccination Report Card (VRC). After any dose of HAVi in all 5 studies, temperatures and injection-site AEs were collected for Days 1-to-5 and systemic AEs were collected for Days 1-to-14. Studies 3, 4, and 5 had uniform injection-site AE collection practices using a validated VRC that prompted daily for injection-site AEs, while studies 1 and 2 had local reactions recorded by investigators only if deemed clinically important. This difference led to a potential underestimation of injection-site AE rates in studies 1 and 2. SAEs, including death due to any cause, were collected in all 5 studies.

No specific immunogenicity hypothesis was evaluated for this integrated analysis. Serum was collected after the first and second doses of HAVi in Study 2 and only after the second dose of HAVi in Studies 4 and 5. Immunogenicity data were combined across these 3 studies.

Vaccine description

Each 0.5 mL dose of HAVi contains approximately 25 U of hepatitis A virus antigen adsorbed onto approximately 0.225 mg of aluminum, provided as amorphous aluminum hydroxyphosphate sulfate, and 35 mcg of sodium borate as a pH stabilizer, in 0.9% sodium chloride. HAVi was to be used as supplied and administered according to the instructions in the product insert. Concomitant vaccines are described in the Supplemental Material.

Safety endpoints

The safety variables of primary interest for all 5 studies were solicited injection-site AEs (injection-site erythema, pain and swelling), unsolicited injection-site AEs occurring at an incidence ≥ 1%, unsolicited systemic AEs occurring at an incidence ≥ 1%, elevated body temperatures (defined as ≥ 38.0°C [≥ 100.4°F] oral equivalent) and SAEs. Safety results were categorized into 3 groups: (1) recipients of HAVi alone, (2) recipients of HAVi given concomitantly with other vaccines, and (3) all recipients of HAVi.

Immunogenicity endpoints

The data from the 3 concomitant use studies (Studies 2, 4 and 5) were combined to evaluate the immunogenicity of HAVi in healthy 12-to-23 month old children administered at the same visit as other pediatric vaccines. The primary immunogenicity endpoints for this integrated summary were the seroconversion rate (SCR, defined as the percent of initially seronegative participants [baseline anti-HAVi titer < 10 mIU/mL] with a post-vaccination anti-HAVi titer ≥ 10 mIU/mL) and the GMT; however, no specific hypotheses were evaluated. The primary analysis population for the integrated immunogenicity summaries was the per-protocol population.

In Study 2, two assays were used to test for hepatitis A antibodies. The modified HAVAB™ assay was used initially before the manufacturer discontinued its production in 2000. Approximately 75% of the serum samples in Study 2 were tested by the modified HAVAB™ method. The modified HAVAB™ kit was replaced with an in vitro Enzyme Immunoassay (EIA) kit supplied by DiaSorin (ETI-AB-HAVK PLUS), and given the name Quantitative HAVK PLUS. The modified HAVAB™ and the Quantitative HAVK PLUS assays were shown to be concordant.[data not shown] The remaining 25% of serum samples from Study 2 and all samples from Studies 4 and 5 were tested using the Quantitative HAVK PLUS.

Statistical analyses

No formal statistical comparisons of the safety data were made between the combined data for the participants who received HAVi alone versus the combined data for those who received HAVi concomitantly with other vaccines, since these comparisons were not pre-established in the study protocols and the participants were not randomized in all studies. Comparisons were made between concomitant and non-concomitant groups within Studies 2, 4, and 5 where participants were randomized by group.

Blood samples for immunogenicity measurements were collected after the first and second doses of HAVi in Study 2 and after only the second dose of HAVi in Studies 4 and 5. For all studies and time points (Post-dose 1 and Post-dose 2), SCR and GMT are presented along with their associated 95% CIs. The confidence intervals for the SCR were computed using the exact confidence interval method for a single binomial proportion.³² The confidence intervals for the GMTs were based on the natural log-transformed titers and the t-distribution.

Funding Statement

Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Acknowledgments

The authors would like to thank:

• All the participants who participated in this study

• VAQTA® Protocol 043 Study Group (Study 1):

• A Werzberger

–VAQTA® Protocol 057 Study Group (Study 2):

–F Guerra, A Werzberger, K Reisinger, E Walter, S Block, S Chartrand (deceased), M Santosham, D Blumberg, J Taylor, H Keyserling, M Sperling, J Bocchini, D Murphey, W Gooch, S Bostrom

–VAQTA® Protocol 066 Study Group (Study 3):

–P Dennehy, K Ramsey, R Mallard, K Zollo, M Lauret, P Lei, K Coopersmith, R Stacks, J Cramer, J Kratzer, E Franklin, A Naz, R Baxter, E Slosberg, J Finnegan, D Newton, H Bernstein, D Johnson

–VAQTA® Protocol 067 Study Group (Study 4):

–R Yetman, J Shepard, W Andrews, M Benhow, H Bertrand, C Chang, A Duke, I Godoy, S Grogg, C Jackson, K Lee, L Sass, L Nassri, D Nelms, T Schechtman, S Senders, B Sullivan, O Shaikh, M Sperling, B Harvey, R Standford Jr, E Barranco, E Goldblatt, W Johnston, P Silas, N Klein, T Crum, M Leonardi, U Goswami, H Bernstein, E Franklin, A Naz

–VAQTA® Protocol 068 Study Group (Study 5):

–K Ramsey, W Abuhammour, R Aguilar, W Andrews, C Ashley, K Bromberg, L Cantor, R Caro, K Concannon, B Congeni, M Cruz, W Daly, O Davis, A Duke, P Giordano, U Goswami, S Grogg, B Harvey, R Hines, A Holmes, K Iqbal, W Johnston, S Kamdar, T Lam, J Lauer, J Leader, M Leonardi, M Levin, G Marshall, D Matthews, D McLaughlin, I Melamed, A Menzel, P Mubarak, M Mufson, C Nassim, D Newton, M Pamaran, W Parker, L Purnell, M Restrepo, D Reynolds, V Sanchez-Bal, M Schear, T Schechtman, R Schwartz, M Severson, S Shapiro, R Sheikh, M Simon, H Soberano, C Spiegel, R Stacks, T Sullivan, P Wisman, R Yogev, M Yudovich, E Zissman

Disclosure of potential conflicts of interest

Funding for this research was provided by Merck & Co., Inc., Kenilworth, NJ, USA (sponsor). All authors work or worked for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and may hold stock and/or stock options in the company. All authors were involved in study concept and design, analysis and interpretation of data, and preparation of this manuscript. FS current affiliation is Philimmune LLC. Although the sponsor formally reviewed a penultimate draft, the opinions expressed are those of the authorship and may not necessarily reflect those of the sponsor. All co-authors approved the final version of the manuscript.