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IMMUNOGENICITY AND SAFETY OF A VARICELLA VACCINE (OKAVAX™) AND A TRIVALENT MEASLES, MUMPS, AND RUBELLA VACCINE (TRIMOVAX™) ADMINISTERED CONCOMITANTLY IN HEALTHY FILIPINO CHILDREN 12–24 MONTHS OLD

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  • 1 Research Institute for Tropical Medicine, Manila, The Philippines, Department of Pediatrics, University of the Philippines, General Hospital, Manila, The Philippines; Aventis Pasteur, Lyon, France

The immunogenicity and safety of Okavax™ varicella vaccine, when administered concomitantly with Trimovax™ measles, mumps, and rubella (MMR) vaccine, were assessed in 300 Filipino children 12–24 months old. Three groups received Okavax only, Trimovax only, or both vaccines concomitantly. In sera obtained six weeks after vaccination, high varicella antibody geometric mean titers (GMTs) (115 and 79.8 mIU/mL, respectively) and seroconversion rates (≥ 91.9%) were similar for Okavax given alone or concomitantly with Trimovax. High MMR GMTs and seroconversion rates (mumps ≥ 94.6%, measles and rubella ≥ 98.6%) were not affected by concomitant administration of Trimovax with Okavax. Solicited local and systemic reactions recorded by parents were slightly more numerous after concomitant administration, but the majority of all reactions were mild and transient. The good tolerance and high immunogenicity observed supports the concomitant administration of Okavax and Trimovax to children in their second year of life to protect against four life-threatening diseases while simplifying childhood immunization programs.

INTRODUCTION

Measles, mumps, rubella, and varicella are infectious diseases with a global distribution. Measles causes significant morbidity and high mortality, especially in developing countries, and is the leading cause of vaccine preventable deaths in children.1 Mumps and rubella virus infections usually result in mild disease but complications and deaths occur and their burden should not be underestimated.2

The development of effective measles, mumps, and rubella (MMR) vaccines and their incorporation into immunization programs has resulted in significant control of these diseases worldwide. In the United States, a decrease of more than 99% in the number of cases of measles, mumps, rubella, and congenital rubella syndrome has been achieved compared with the prevaccination era,3 and the Expanded Program of Immunization of the World Health Organization (WHO) continues to prevent millions of deaths from measles in developing countries each year.4 The WHO has targeted measles, mumps, and rubella for eradication through vaccination.5 In some countries, the incidence of these diseases has been greatly reduced and in some elimination has already been achieved.3,6,7

Varicella, generally a benign childhood disease, is more serious in adolescents and adults and can lead to severe, even fatal, complications in both children and adults. In the United States, there are an estimated 9,300 varicella-related hospitalizations annually with the highest case-fatality rates occurring in infants (6.23/100,000) and in adults 30–49 years old (25.2/100,000).8 In the Philippines, the corresponding statistics are an incidence rate of 47.8/100,000, 35,700 hospitalizations annually, and a case-fatality rate of 0.082/100,000 population. Oka strain varicella vaccines were first developed more than 25 years ago and have been shown to be safe and immunogenic,9–11 and have recently been included in mass vaccination programs in some countries. Vaccination has been shown to be highly effective in preventing serious varicella disease, even though mild cases of disease do occur in a small percentage of vaccines.12,13

Despite the successes of these vaccines, there are signs that decreases in vaccine coverage, especially for measles, mumps, and rubella, have occurred in some countries and this has resulted in a resurgence of cases.14–18 Simplification of vaccination programs could increase compliance and thus help to maintain the required high levels of vaccine coverage. One way this could be achieved is by the administration of two or more vaccines at the same visit. Many countries recommend that MMR vaccine and varicella vaccine are given to children in their second year of life; thus, these vaccines are candidates to be administered at the same visit. The varicella vaccine, Okavax, which is derived from the Oka strain varicella-zoster virus (VZV), and the combined MMR virus vaccine, Trimovax, have already been administered to millions of children and proven to be safe and efficacious. The aim of this study was to assess the immunogenicity and safety of Okavax and Trimovax when administered concomitantly in children 12–24 months of age.

MATERIALS AND METHODS

Subjects and study design.

This open, randomized study was conducted in Manila, the Philippines from January 31, 2000 to September 28, 2000 after review and approval of the protocol by the Institutional and Ethic Review Board of the Research Institute for Tropical Medicine in Manila. The study was conducted according to the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines.

Healthy children of both sexes from 12 to 24 months of age were included in the study after written informed consent was obtained from their parents or guardians. Children with any of the following were excluded from the study: history of clinical varicella, measles, mumps, or rubella infection or contact with these diseases in the preceding 4 weeks, previous varicella, measles, mumps or rubella vaccination; allergy to any component of the vaccines including egg proteins or gelatin, or any condition related to contraindications to the vaccines; chronic and severe illness, congenital or acquired immunodeficiency; vaccine administration or use of blood, blood derivatives, immunoglobulins, immunosuppressors, or immunomodulators within the period from 90 days prior to vaccination (30 days for vaccines) to 42 days after vaccination; treatment with aspirin or steroids at doses sufficient, in the investigator’s opinion, to significantly alter systemic immunity; acute or febrile illness (axillary temperature > 37.5°C) within 72 hours before vaccination; and simultaneous or planned participation in another clinical study.

Children enrolled into the study were randomly assigned into one of three equal groups at the first study visit, and the vaccine(s) were administered after a physical examination and collection of a prevaccination blood sample. A second blood sample for evaluation of immune response was collected on day 42 (± 5 days) after vaccination.

Vaccines.

Subjects assigned to treatment group A received the live attenuated Oka strain varicella-zoster virus vaccine Okavax (Varicella Biken®; The Research Foundation for Microbial Diseases of Osaka University, Osaka, Japan) by subcutaneous injection in the thigh. The potency of the Okavax vaccine after reconstitution with the distilled water diluent is not less than 1,000 plaque-forming units per 0.5-mL dose. Treatment group B received the combined live attenuated measles, mumps, rubella virus vaccine Trimovax (Aventis Pasteur, Lyon, France), by intramuscular injection in the thigh. Each dose of the lyophilized Trimovax vaccine reconstituted in 0.5 mL of saline diluent contains at least 1,000 50% tissue culture infectious doses (TCID50) of Schwarz strain measles virus, at least 5,000 TCID50 of Urabe AM 9 strain mumps virus, and at least 1,000 TCID50 of Wistar RA 27/3M strain of rubella virus. Treatment group C received concomitant injections of Okavax (subcutaneously) and Trimovax (intramuscularly) in opposite thighs. Commercial batches of each vaccine were used in the study.

Laboratory assays (serologic assays/serology).

Separated pre- and post-vaccination serum samples, kept at −20°C, were sent to Aventis Pasteur Clinical Immunology Platform (Val de Reuil, France) where the serologic assays were performed in a blinded manner. Antibody levels to measles, mumps, and rubella were measured by enzyme-linked immunosorbent assays (ELISAs) using commercial kits (Enzygnost® Anti-Measles Virus/IgG, Enzygnost® Anti-Parotitis Virus/IgG for Mumps, and Enzygnost® Anti-Rubella virus/IgG; Behring, Marburg, Germany). IgG antibodies to VZV were measured in paired serum samples at an initial dilution of 1:100 using a glycoprotein ELISA; the reference serum (British Standard for varicella-zoster antibody, 90/690; National Institute for Biological Standards and Control, South Mimms, United Kingdom) and quality control samples were tested in parallel. Concentrations of antibody to VZV were determined by reference to the calibration curve of the reference serum and expressed in mIU/mL.

Safety.

All subjects were monitored at the study center for immediate reactions during the first 30 minutes postvaccination. Each subject’s family was supplied with a transparent bangle for local reaction measurement and a diary card to record any local and systemic adverse events throughout the following 42-day period, with particular attention being made to events occurring during the first three days after vaccination. Specific adverse events solicited on the card were local pain, redness, induration, and swelling, as well as systemic events: fever (axillary temperature ≥ 36.6°C), rash, pruritus, purpura, and parotid gland swelling.

Statistical analysis.

This was a descriptive study. However, sample size calculations showed that with a seroconversion rate of at least 94%, 75 subjects per group would provide a satisfactory level of precision of the 95% confidence interval (CI) (lower limit ≥ 87%).

Seroconversion was defined as the presence of an antibody level higher than the respective assay cut-off value (varicella = 12 mIU/mL, measles = 300 mIU/mL, mumps = 500 U/mL, rubella = 8 IU/mL) in an initially seronegative subject (i.e., a subject who presented with an antibody level lower than the cut-off value before vaccination). Seroconversion rates and geometric mean titers (GMTs) of antibodies to varicella, measles, mumps, and rubella, each with their 95% CI, were calculated at day 42 postvaccination in initially seronegative subjects.

The numbers and percentages of subjects with at least one immediate reaction (occurring within 30 minutes of vaccination), one delayed local reaction, or one delayed systemic event (each occurring within 42 day following vaccination), as well as the frequencies of each different type of event, were calculated for all treatment groups.

RESULTS

Immunogenicity.

A total of 300 subjects with a mean age of 17.7 months (range = 12.0–24.8 months) were enrolled in the study (Table 1). No subjects violated the exclusion criteria and all received their respective vaccines according to the randomization procedure. Reactogenicity data were not available for 10 subjects who did not return for the second visit. Blood samples were not available for an additional seven subjects who returned for the second visit, four subjects due to parental refusal of the blood drawing and three subjects who attended more than 105 days after vaccination. The different numbers of subjects in the immunogenicity analyses for the different antigens reflect those subjects who were excluded from these analyses because they were seropositive before vaccination.

For each of the four antigens, the seroconversion rates were similar, whether the vaccines were given alone or concomitantly (Table 2). Seroconversion rates for varicella were 95.7% (95% CI = 89.5, 98.8) when Okavax was given alone or 91.9% (95% CI = 83.9, 96.7) when given concomitantly with Trimovax. Postvaccination anti-varicella GMTs were somewhat lower when Okavax was given concomitantly with Trimovax (79.8 mIU/mL) than when given alone (115 mIU/ mL), although both were considerably higher than the predefined seroconversion GMT of 12 mIU/mL for varicella. Seroconversion rates were ≥ 94.6% for mumps and ≥ 98.6% for measles and rubella whether Trimovax was given alone or concomitantly with Okavax (Table 2).

Postvaccination GMTs of antibodies against measles, mumps, and rubella were similar in the groups given Trimovax only, or as a concomitant vaccination with the varicella vaccine. The 95% CI indicate that there would be no significant differences if these had been tested.

Safety.

All local reactions in all three treatment groups occurred within three days of vaccination, with the majority occurring within 30 minutes of injection. These lasted for 24 hours or less and were considered to be mild in intensity. As shown in Table 3, redness was the most frequent immediate reaction (≤ 37% at Okavax sites and ≤ 11% at Trimovax sites) and pain the most frequent delayed reaction at all injection sites (≤ 13% at Okavax sites and ≤ 7% at Trimovax sites). The rates of local reactions at the Trimovax injections sites were similar when the vaccine was given alone or with Okavax. However, fewer reactions were reported at the Okavax injection site when the vaccine was given alone rather than concomitantly with Trimovax. Only two severe local reactions were reported; both cases of redness at the Okavax site with a diameter > 5 cm that lasted for less than one day. One case occurred in a subject given Okavax alone and one concomitantly with Trimovax.

Systemic events considered by the investigator to be possibly, probably, or definitely related to the vaccines were reported slightly more frequently following concomitant Okavax and Trimovax (36.2%) than either Okavax (33.7%) or Trimovax (31.6%) given alone (Table 3). Fever was the most frequently reported systemic event in all groups (≤ 36.2% in all groups). This high incidence of fever may, in part, be explained by the broad fever definition used in this study (axillary temperature ≥ 36.6°C within 42 days after vaccination) because most cases of fever were mild (≤ 37.6°C). Fever usually occurred within three days of vaccination and lasted seven days or less. Rashes and other systemic events were reported very infrequently. There were only six severe systemic events considered to have a relationship to the vaccines. Severe fever (all ≤ 39.5°C) in three subjects after Trimovax alone occurred on days 1 or 2 and lasted for four days or less. In the concomitant group, severe fever occurred in one subject, severe fever and rash associated with measles in another, and cough and a severe rash associated with measles in a third subject. A serious adverse event was reported in this last subject who was hospitalized 10 days after vaccination with pneumonia and recovered without sequelae. The event was considered by the investigator to be post-immunization measles pneumonia. However, there was a measles outbreak in the study area at the time of the event and the causative agent was not identified so it is difficult to be sure that the event was definitely linked to the vaccine.

DISCUSSION

The growing number of effective and important vaccines that have to be included in current routine childhood immunization programs create substantial economic problems and logistic difficulties, which may result in missed vaccinations. The benefit of using combination vaccines (i.e., several immunogens physically combined in a single preparation and administered in a single injection) and/or concomitant vaccines (i.e., two or more vaccines administered at different sites at the same visit) as a means of simplifying immunization programs is well recognized. However, when vaccines are administered in this way their efficacy or immunogenicity and safety must not be jeopardized.

In the present study, the control group given Trimovax alone displayed immunogenicity in terms of seroconversion rates and GMTs for measles, mumps, and rubella, which was similar to published data.19–23 Furthermore, the immune response was not different when Trimovax was administered alone or concomitantly with Okavax. Varicella seroconversion rates were similar when Okavax was administered alone or concomitantly with Trimovax and were similar to those already published for Okavax given separately.9,24 The only noticeable effect of concomitant administration was the lower post-vaccination anti-varicella GMT in the concomitant group than the Okavax group. However, in view of the high anti-varicella antibody titers achieved in both groups, it is debatable whether this small difference is important since its clinical relevance is unknown.

Several studies reported in the literature have compared the immunogenicity of measles, mumps, rubella, and varicella (MMRV) combination vaccines with MMR and varicella vaccines given separately. In general, although these studies used different vaccines to the ones used in this study, they showed that the combination vaccines produced much lower varicella seroconversion rates and GMTs than the varicella vaccine given alone, while measles, mumps, and rubella responses were similar to those seen when MMR was given alone. After these first studies, it was concluded that the MMR vaccine interfered with the varicella immune responses but not vice versa, and it was suggested that vaccines with a high potency of varicella and a low potency MMR might overcome this problem.25–27 Comparisons of more recent formulations of MMRV combination vaccines with MMR and varicella vaccine given concomitantly have shown uniformly high rates of seroconversion with no real reduction in elicited antibody titers (compared with separate vaccines) except for the varicella titers, which were twice as high in the concomitant groups as in the combination groups.28,29 These findings are important when the inverse correlation between the six-week varicella titer and the likelihood of development of modified varicella-like syndrome is considered.30,31 The satisfactory seroconversion rates observed in this study following immediate sequential administration of these vaccines suggests that earlier reductions in anti-varicella titers observed in combined vaccines may have resulted from some characteristic of the formulations themselves rather than immune failure on the part of the recipients.

The reactogenicity profiles of Trimovax and Okavax given separately in this study are consistent with published data for these vaccines.9,22–24 Approximately 40% of the subjects vaccinated with concomitant Trimovax and Okavax in this study experienced local reactions or systemic events. Nearly all the local reactions were mild and transient, while most of the systemic events were not only of the type expected to occur commonly in children of this age group, but most were considered to be unrelated to vaccination. Such a high prevalence of temporally rather than causally related adverse events has already been observed for MMR vaccine.32 In this study, as has already been reported previously with concomitant MMR and varicella vaccines, mild fever was the most frequently reported systemic event. Skin rashes, which occurred in more than 5% of subjects in other studies, occurred very infrequently in this study.29

In this study, a small increase was seen in adverse events after concomitant administration of Trimovax and Okavax compared with the separate administration of the vaccines. Similar increases in adverse events have been reported following the concomitant administration of other vaccines, including MMR vaccines, and it has been stated in the literature that “…adverse events after the concurrent administration of multiple vaccines generally are increased only modestly, if at all, compared with events after the administration of the most reactogenic vaccine alone.”33

The benefits of administering Okavax and Trimovax concomitantly rather than separately are illustrated by this study. Clinical immunogenicity was not compromised and the very modest increase in mainly mild and transient adverse events is balanced by the decrease in the number of visits required that would be anticipated to improve parental compliance and an increased overall comfort for the vaccinees.

Although there is no evidence that the efficacy of any recommended childhood vaccine is altered by concomitant administration with other vaccines licensed for administration at the same age,34 it is apparent that the protection afforded by vaccines given in this way cannot be predicted accurately. Further data on the persistence of measles, mumps, rubella, and varicella antibody titers could help to provide evidence of the long-term protection provided by the concomitant administration of these vaccines.

Table 1

Age of subjects and numbers included in the analyses

OkavaxOkavax and Trimovax given concomitantlyTrimovax
* For each antigen, initially seropositive subjects were removed from the analysis. This is reflected in the different numbers of subjects in the immunogenicity analyses for the different antigens.
Numbers of subjects enrolled: all included in immediate safety analysis100100100
Mean age, months17.917.018.1
Age range12.1–24.812.0–24.812.0–24.7
Numbers of subjects included in delayed safety analysis989498
Numbers of subjects eligible for inclusion in immunogenicity analysis*969295
Table 2

Seroconversion rates and GMTs at six weeks postvaccination for initially seronegative vaccinees*

OkavaxOkavax and Trimovax given concomitantlyTrimovax
No.ResponseNo.ResponseNo.Response
* No. = number of initially seronegative subjects included in the analysis; SCR = seroconversion rate; CI = confidence interval; GMT = geometric mean titer.
Varicella9486
    SCR (%)95.791.9
    95% CI89.5–98.883.9–96.7
    GMT (mIU/mL)11579.8
    95% CI94.5–14063.8–99.9
Mumps8292
    SCR (%)95.194.6
    95% CI88.0–98.787.8–98.2
    GMT (U/mL)2,0731,827
    95% CI1,670–2,5731,516–2,201
Measles7571
    SCR (%)98.798.6
    95% CI92.8–10092.4–100
    GMT (mIU/mL)3,6963,011
    95% CI3,138–4,3522,599–3,489
Rubella7984
    SCR (%)10098.8
    95% CI95.4–10093.5–100
    GMT (IU/mL)106112
    95% CI91.0–12294.4–132
Table 3

Percentages of subjects with local reactions and systemic adverse events with some relationship to vaccination*

Okavax and Trimovax given concomitantly
OkavaxOkavax siteTrimovax siteTrimovax
No.%No.%No.%No.%
* No. = number of subjects included in the analysis. All 300 enrolled were included in the analysis of immediate local reactions for 30 minutes after vaccination. Only the 292 subjects returning for visit 2 were included in the assessment of delayed local reactions and systemic events.
† Immediate reactions defined as occurring within 30 minutes of injection.
‡ Delayed reactions defined as occurring 30 minutes to 42 days after injection.
§ Systemic events occurring within 42 days after injection and considered by the investigator to be possibly, probably, or definitely related to the vaccines.
Subject with at least one immediate reaction†10040.010042.010.010013.0
    Induration9.08.002.0
    Local pain9.07.05.01.0
    Redness37.035.06.011.0
Subject with at least one delayed local reaction‡988.29416.09410.6989.2
    Induration05.35.31.0
    Local pain5.112.86.47.1
    Redness3.16.45.33.1
    Swelling04.33.23.1
Subject with at least one related systemic event§9833.79436.29831.6
    Fever (axillary temperature ≥ 36.6°C)33.736.231.6
    Rash02.10
    Coughing01.10
    Viral infection (measles)02.10

Authors’ addresses: Salvacion Gatchalian, Charissa Tabora, and Nancy Bermal, Research Institute for Tropical Medicine, Filinvest Corporate City, Alabang, Muntilupa, The Philippines. Didier Leboulleux, Aventis Pasteur, 24/F, DCH Commercial Centre, 25 Westlands Road, Quarry Bay, Hong Kong, Telephone: 852-2506-8421. Eric Desauziers, Aventis Pasteur, 2 Avenue Pont Pasteur, 69007 Lyon, France, Telephone: 33-4-37-37-73-84.

Acknowledgments: We are grateful to V. Canouet, Professor M. Crisostomo, C. Deroche, I. Durot, and R. Mate for their expertise in the performance of this study.

Financial support: This study was supported by Aventis Pasteur (Lyon, France).

Disclaimer: Didier Leboulleux and Eric Desauziers are employees of Aventis Pasteur.

REFERENCES

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    Redd S, Markowitz L, Katz S, 1999. Measles vaccine. Plotkin SA, Orenstein WA, eds. Vaccines. Third edition. Philadelphia: W. B. Saunders, 222–250.

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Author Notes

Reprint requests: Salvacion Gatchalian, Research Institute for Tropical Medicine, Filinvest Corporate City, Alabang, Muntilupa, The Philippines, Telephone: 63-2-809-7599, Fax: 63-2-842-2245, E-mail: edsal@impactnet.com.
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