ARTICLE Comprison of the Sfety nd Immunogenicity of Refrigertor-Stble Versus Frozen Formultion of ProQud (Mesles, Mumps, Rubell, nd Vricell Virus Vccine Live) Henry H. Bernstein, DO, Kren Eves, BS b, Kristy Cmpbell, MS b, Steven B. Blck, MD c, Jerry D. Twiggs, MD d, Keith S. Reisinger, MD e, Rlph M. Conti, MD f, Crl-Erik Flodmrk, MD g, Lrs Rombo, MD h, Stephnie Klopfer, PhD b, Florin Schödel, MD b, Jonthn Hrtzel, PhD b, Brbr J. Kuter, PhD, MPH b, nd the Refrigertor-Stble Formultion Study Group for ProQud Drtmouth Medicl School, Children s Hospitl t Drtmouth, Lebnon, New Hmpshire; b Merck Reserch Lbortories, West Point, Pennsylvni; c Kiser Permnente Vccine Study Center, Oklnd, Cliforni; d Dixie Peditrics, St George, Uth; e Primry Physicins Reserch, Pittsburgh, Pennsylvni; f Foothills Peditrics, Henderson, Nevd; g Deprtment of Peditrics, University Hospitl, Universitetssjukhuset MAS, Mlmö, Sweden; h Deprtment of Infectious Diseses, Mlrsjukhuset, Eskiltun, Sweden Finncil Disclosure: Drs Bernstein, Blck, Conti, Twiggs, Flodmrk, nd Rombo nd the Refrigertor-Stble Formultion Study Group for ProQud prticipted in this reserch study, which ws sponsored by Merck & Co, Inc. Drs Reisinger nd Keyserling lso prticipted in this reserch study nd re spekers for Merck & Co, Inc. ABSTRACT OBJECTIVE. A refrigertor-stble formultion of ProQud hs been developed to expnd the utility of ProQud to res in which mintennce of frozen cold chin ( 15 C or colder) during storge nd trnsport my not be fesible. The objective of this study ws to demonstrte tht the immunogenicity nd sfety profiles of refrigertor-stble formultion of ProQud re similr to the recently licensed frozen formultion. METHODS. In this double-blind, rndomized, multicenter study, helthy 12- to 23- month-old children with negtive vccintion nd clinicl histories for mesles, mumps, rubell, vricell, nd zoster were vccinted with either the refrigertorstble formultion of ProQud (N 1006) or the frozen formultion of ProQud (N 513). Ptients were followed for 42 dys fter vccintion for dverse experiences. Immunogenicity ws evluted 6 weeks fter vccintion. RESULTS. The refrigertor-stble formultion of ProQud ws generlly well tolerted. The incidence of dverse experiences ws similr between groups. No vccine-relted serious dverse experiences were reported. For both groups, the response rte ws 97.7% for mesles, mumps, nd rubell, nd the percentge of ptients with vricell zoster virus ntibody titer of 5 U/mL glycoprotein ntigen-bsed enzyme-linked immunosorbent ssy fter vccintion ws 88.8%. The geometric men titers for ll ntigens were numericlly slightly higher in ptients who received the refrigertor-stble formultion. CONCLUSIONS. The refrigertor-stble formultion of ProQud is generlly well tolerted, highly immunogenic, nd noninferior in terms of postvccintion ntibody responses. This refrigertor-stble formultion my improve ese of vccine dministrtion, increse use of the vccine throughout the world becuse of its improved storge conditions, nd replce the frozen formultion of ProQud or ny dose of M-M-RII nd Vrivx in routine prctice. www.peditrics.org/cgi/doi/10.1542/ peds.2006-2283 doi:10.1542/peds.2006-2283 Key Words mesles, mumps, rubell, vricell, vccine, ProQud, Vrivx, M-M-RII, immuniztion Abbrevitions VRC vccintion report crd VZV vricell zoster virus ELISA enzyme-linked immunosorbent ssy gpelisa glycoprotein ntigen bsed enzyme-linked immunosorbent ssy GMT geometric men titer CI confidence intervl Accepted for publiction Nov 21, 2006 Address correspondence to Henry H. Bernstein, DO, Generl Acdemic Peditrics, Drtmouth Hitchcock Medicl Center, 1 Medicl Center Dr, Lebnon, NH 03756. E-mil: henry.bernstein@hitchcock.org PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2007 by the Americn Acdemy of Peditrics e1299
IN THE UNITED Sttes nd other countries, M-M-RII (Merck & Co, Inc, West Point, PA) hs been highly effective in reducing the incidence of mesles, mumps, nd rubell. 1 3 To dte, vccintion rtes ginst mesles, mumps, nd rubell hve reched 93% in the United Sttes nd re generlly high in most developed countries. 1,4 6 Routine use of Vrivx (Merck & Co, Inc) in the United Sttes hs resulted in substntil reduction in the incidence of vricell. 7,8 However, vccintion rtes ginst vricell hve reched only 87.5% in the United Sttes despite Advisory Committee on Immuniztion Prctices recommendtions in 1996 for universl use in young children. Vrivx is not currently recommended in most other countries. 6 ProQud is combined mesles, mumps, rubell, nd vricell virus vccine developed by Merck & Co, Inc. Concerns regrding n lredy complex vccintion schedule nd dditionl costs to both prents nd helth cre providers re notble obstcles surrounding vccine dministrtion. 9 As combintion vccine, ProQud is expected to decrese the number of injections tht re given to children nd ultimtely improve complince nd immuniztions rtes for the 4 diseses worldwide. 9 The frozen formultion of ProQud, licensed in the United Sttes nd Europe, hs been shown to be s immunogenic nd generlly well tolerted s its component vccines, M-M-RII nd Vrivx, nd is strting to be widely used in the United Sttes. 10,11 However, its utility is limited to geogrphic res where frozen cold chin ( 15 C or colder) during trnsport nd storge in clinics, phrmcies, nd physicins offices cn be mintined. Mintining refrigerted cold chin (2 8 C), s is done with most other vccines, would be fesible in much lrger prt of the world. Becuse of this, Merck & Co, Inc, hs developed refrigertor-stble formultion of ProQud, incorporting 2.5 mg of ure-bsed stbilizer in ech dose. The effect of this stbilizer on immunogenicity nd sfety profiles ws previously evluted in clinicl study of Vrivx (vricell virus vccine live [Ok/Merck]). Both Vrivx formultions, with nd without the stbilizer, were generlly well tolerted, were comprble with respect to the occurrence of injection-site nd systemic dverse experiences, nd were highly immunogenic. 12 The purpose of this study ws to demonstrte tht the immunogenicity nd the sfety of refrigertor-stble formultion of ProQud re similr to the recently licensed frozen formultion. This study removes 1 brrier to effective vccine delivery by lessening the burden for helth cre professionls of the storge nd hndling of frozen vccines. 13 METHODS Study Ptients This study ws pproved by the institutionl review bord/independent ethics committee of ech of the 32 prticipting sites. The study sites consisted of cdemic institutions, regionl nd peditric medicl centers, mnged cre orgniztions, nd privte physicin offices, with 30 sites in the United Sttes nd 2 sites in Sweden. The study ws conducted from September 2002 through June 2003. Written informed consent ws obtined from the prent/legl gurdin of ech ptient before enrollment. Helthy 12- to 23-month-old children with negtive vccintion nd clinicl histories for mesles, mumps, rubell, vricell, nd zoster were eligible to prticipte. Ptients were excluded for ny of the following resons: previously received mesles, mumps, rubell, nd/or vricell vccine either lone or in combintion; immunodeficient or receiving immunosuppressive therpy; history of seizure disorder; known llergy to ny vccine component; recent exposure to mesles, mumps, rubell, vricell, nd/or zoster; receipt of ny inctivted nonstudy vccines within 14 dys or live nonstudy vccines within 30 dys before enrollment; receipt of immune globulin or blood products within the 5 months before enrollment or hd scheduled to receive such products within 42 dys fter vccintion; or, in the opinion of the investigtor, hd ny condition tht would hve interfered with study objectives. Vccine/Rndomiztion Ptients were rndomly ssigned t 2:1 rtio to receive either the refrigertor-stble or the frozen formultion of ProQud on dy 1. All clinicl mterils were mnufctured by Merck & Co, Inc. ProQud is sterile, lyophilized qudrivlent vccine tht fter reconstitution is dministered s 0.5-mL subcutneous injection. This study ws double blind with regrd to tretment group. The prent/legl gurdin of the ptient, the study personnel who dministered the vccine nd hndled ll sfety nd serologic follow-up, nd sponsor personnel were blinded to which vccine formultion ech ptient received. Becuse of obvious differences in vccine storge conditions nd slight differences in ppernce, the vccines tht were used in this study were prepred nd ccounted for by n unblinded third prty who ws otherwise not involved in the conduct of the study. Sfety Surveillnce Prents/legl gurdins were sked to record on vccintion report crd (VRC) their child s dily temperture (xillry), ll locl nd systemic dverse experiences, nd ny other vccines or medictions dministered both on the dy of vccintion nd for 41 dditionl dys fter vccintion. Prents/legl gurdins were sked to notify study personnel immeditely if their child experienced mesles, mesles-like rsh, rubell, rubell-like rsh, vricell, vricell-like rsh, zoster, zoster-like rsh, mumps, or mumps-like symptoms or if ny serious dverse experience occurred. See1300 BERNSTEIN et l
rious nd vccine-relted dverse experiences were followed to resolution. Prents/legl gurdins were instructed to mesure the ptient s rectl temperture if the ptient s xillry temperture ws 98.6 F ( 37.0 C). When ptient s temperture ws 102 F ( 38.9 C) orl or equivlent ( 101 F [ 38.3 C] xillry or 103 F [ 39.4 C] rectl), study personnel recorded the fever s n dverse experience. The prent/ legl gurdin ws responsible for evluting the mximum intensity of ech dverse experience. Locl dverse experiences of swelling nd redness were evluted by mximum size. The investigtor ssessed ech reported dverse experience s to seriousness, ction tken, nd cusl reltionship to study vccine. Lbortory Methods A 5- to 10-mL blood smple ws collected immeditely before nd 6 weeks fter vccintion. To determine mesles, mumps, rubell, nd vricell zoster virus (VZV) ntibody levels, serum smples were tested by Merck Reserch Lbortories (West Point, PA) using ppropritely sensitive enzyme-linked immunosorbent ssy (ELISA) methods for mesles, mumps, nd rubell nd glycoprotein ntigen bsed enzyme-linked immunosorbent ssy (gpelisa) for VZV. 14 16 Serum smples with ntibody levels 255 miu/ml for mesles, 10 ntibody U for mumps, 10 IU/mL for rubell, nd 1.25 gpelisa U/mL for VZV were considered to be seronegtive. For mesles, mumps, nd rubell, the ntibody response rtes were defined s the proportion of ptients who were seronegtive before vccintion nd becme seropositive fter vccintion. The ntibody response rte for VZV ws defined s the proportion of ptients who were seronegtive t bseline nd whose postvccintion titer ws 5 gpelisa U/mL. A VZV postvccintion titer 5 gpelisa U/mL hs been previously shown to be highly correlted with long-term protection. 17,18 Sttisticl Methods The primry immunogenicity nlysis ws performed on per-protocol bsis. The nlysis of ntibody response rtes to ech vccine ntigen ws bsed on the noninferiority test developed by Miettinen nd Nurminen 19 with study center strtifiction. Noninferiority of geometric men titers (GMTs) ws bsed on n nlysis of vrince model of log-djusted titers for ech ntigen with study center strtifiction. To conclude noninferiority of the refrigertor-stble formultion of ProQud (using 1-sided.025 significnce level), the response rtes could be no more thn 5 percentge points lower for mesles, mumps, nd rubell nd no more thn 10 percentge points lower for VZV. The GMTs could be no more thn 1.5-fold lower for ll ntigens. In ddition, it could be concluded tht the refrigertor-stble formultion of ProQud induced cceptble ntibody response rtes when the lower bound of the 95% confidence intervl (CI) for ech ntigen ws entirely bove the prespecified criteri (90% for mesles, mumps, nd rubell nd 76% for vricell). Success of the tril required stisfction of ll 3 immunogenicity hypotheses. To ddress the primry hypothesis regrding sfety, we compred the sfety profiles of the refrigertor-stble nd frozen formultions of ProQud. For injection-site dverse experiences tht occurred on dys 1 to 5 fter vccintion nd for specific systemic clinicl dverse experiences tht occurred on dys 1 to 42 fter vccintion, risk differences were estimted, nd the 95% 2-sided CI ws provided. For dverse experiences tht specificlly were prompted for on the VRC, including injection-site redness, injection-site swelling, injection-site pin/tenderness, mesles-like rshes, rubell-like rshes, vricell-like rshes, zoster-like rshes, nd mumps-like symptoms, s well s the incidence of elevted temperture (defined s 102 F [ 38.9 C] orl equivlent), the corresponding P vlues were provided. RESULTS Study Popultion A totl of 1519 helthy children, 12 to 23 months of ge, were vccinted with either the refrigertor-stble formultion (N 1006) or the frozen formultion (N 513) of ProQud. At vccintion, both groups were comprble with respect to gender, ge, nd rce; 50% of ptients were femle, nd 73% were white. The men ge ws 13.3 months t study entry. Sfety No vccine-relted serious dverse experiences were reported within the follow-up period. The overll rte of serious dverse experiences between recipients of the refrigerted nd frozen formultions of ProQud ws not sttisticlly significnt (0.7% nd 0.4%, respectively). All serious dverse experiences were medicl conditions tht re generlly expected of peditric popultion. The serious dverse experiences tht were reported by the 7 ptients who received the refrigertor-stble formultion were respirtory syncytil virus infection, pneumoni, dehydrtion, phryngitis, gstroenteritis, nd ccidentl exposure. The serious dverse experiences tht were reported by the 2 ptients who received the frozen formultion were gstroenteritis, pneumoni spirtion, nd neuroblstom. The ptient with neuroblstom did not receive the dignosis until 5 dys fter vccintion nd continued in the study with no dditionl dverse experiences reported. Tble 1 summrizes the specific injection-site dverse experiences tht were reported dys 1 to 5 fter vccintion. Overll, the proportion of ptients who reported injection-site dverse experiences ws comprble between the tretment groups. Injection-site dverse ex- e1301
TABLE 1 Injection-Site Adverse Experiences 1 to 5 Dys After Administrtion of ProQud Prmeter Refrigertor-Stble (N 1006), n (%) Frozen (N 513), n (%) Risk Difference (Refrigertor-Stble Frozen), % (95% CI) Ptients with 1 injection-site 370 (37.6) 190 (38.0) NA NA dverse experience Injection-site erythem c 175 (17.8) 90 (18.0) 0.2 ( 4.5 to 3.8) 0.93 Injection-site hemorrhge 15 (1.5) 6 (1.2) 0.3 ( 1.2 to 1.5) NA Injection-site pin c 291 (29.6) 152 (30.4) 0.8 ( 5.8 to 4.1) 0.75 Injection-site rsh c 3 (0.3) 3 (0.6) 0.3 ( 1.5 to 0.4) 0.40 Injection-site swelling c 86 (8.7) 46 (9.2) 0.5 ( 3.7 to 2.5) 0.77 Percentges were clculted on the bsis of the number of ptients with follow-up. No risk differences, CIs, nd/or P vlues were plnned. N indictes number of ptients vccinted in ech tretment group; n, number of ptients with n dverse experience; NA, not pplicble. Risk differences nd CIs were bsed on the pooled incidence rtes cross study centers; corresponding P vlues were clculted on the bsis of test of risk differences between the 2 tretment groups. b P vlues re provided only for events tht were prompted for on the VRC nd hve been rounded to the nerest hundredth. c Prompted for on the VRC. P b periences tht were specificlly prompted for on the VRC were erythem, pin, nd swelling nd were the most commonly reported specific injection-site rections ( 10%) in either tretment group. Tble 2 summrizes the overll clinicl nd most frequent ( 5%) specific systemic dverse experiences by tretment group fter vccintion. The proportion of ptients who reported t lest 1 systemic dverse experience ws comprble between the tretment groups. The most frequently reported specific systemic dverse experiences ( 10% in either tretment group) were elevted temperture ( 102 F [ 38.9 C], orl equivlent), upper respirtory trct infection, nsophryngitis, otitis medi/er infection, nd dirrhe. The 2 tretment groups were comprble with respect to the incidence rtes of specific systemic dverse experiences except for 3 dverse experiences. Insomni nd dermtitis were reported in greter number of ptients who received the refrigertor-stble formultion (1.1% nd 1.3%, respectively) s compred with the ptients who received the frozen formultion (0% nd 0.2%, respectively). Fewer ptients who received the refrigertor-stble formultion (0.3%) experienced virl upper respirtory trct infection s compred with ptients who received the frozen formultion (1.2%). The observed proportions of ll ptients who reported these dverse experiences were ll 1.3%, seemed to be of little clinicl relevnce, nd in view of the high number of comprisons mde for sfety end points, could be ttributble to chnce lone. When the rtes of vccine-relted sys- TABLE 2 Systemic Adverse Experiences (>5% in Either Tretment Group) 1 to 42 Dys After Administrtion of ProQud Prmeter Refrigertor-Stble (N 1006), n (%) Frozen (N 513), n (%) Risk Difference (Refrigertor-Stble Frozen), % (95% CI) Ptients with 1 systemic dverse experience 779 (79.2) 400 (80.0) Upper respirtory trct infection 196 (19.9) 104 (20.8) 0.9 ( 5.3 to 3.4) Otitis medi/er infection b 185 (18.8) 101 (20.2) 1.4 ( 5.8 to 2.8) Elevted temperture c 168 (17.1) 86 (17.2) 0.1 ( 4.3 to 3.8) Nsophryngitis 139 (14.1) 79 (15.8) 1.7 ( 5.7 to 2.1) Dirrhe 110 (11.2) 46 (9.2) 2.0 ( 1.4 to 5.1) Dermtitis diper 85 (8.6) 43 (8.6) 0.0 ( 3.2 to 2.9) Cough 78 (7.9) 40 (8.0) 0.1 ( 3.2 to 2.7) Irritbility 73 (7.4) 49 (9.8) 2.4 ( 5.7 to 0.6) Rsh (nonspecific) 72 (7.3) 38 (7.6) 0.3 ( 3.3 to 2.4) Vomiting 67 (6.8) 29 (5.8) 1.0 ( 1.8 to 3.5) Rhinorrhe 65 (6.6) 33 (6.6) 0.0 ( 2.9 to 2.6) Rsh morbilliform 48 (4.9) 32 (6.4) 1.5 ( 4.3 to 0.9) Percentges were clculted on the bsis of the number of ptients with follow-up. There were no significnt differences between the tretment groups for ny dverse experiences shown bove. N indictes number of ptients vccinted in ech tretment group; n, number of ptients with n dverse experience. Risk differences nd CIs were bsed on the pooled incidence rtes cross ll study centers. b Otitis medi nd er infection were reported s seprte dverse experiences but re combined here becuse of similrity in terms. Otitis medi ws reported in 147 (15.0%) ptients who received the refrigertor-stble formultion nd in 76 (15.2%) ptients who received the frozen formultion. Er infection ws reported in 38 (3.9%) ptients who received the refrigertor-stble formultion nd in 25 (5.0%) ptients who received the frozen formultion. c Includes ny temperture 102 F ( 38.9 C), orl equivlent. e1302 BERNSTEIN et l
temic dverse experiences were compred, there were no significnt differences between tretment groups. The proportion of ptients with elevted tempertures ( 102 F [ 38.9 C], orl equivlent) ws comprble between tretment groups. More thn 45% of fevers were reported during dys 6 to 13 fter vccintion. The mjority of the fever episodes were clssified s either mild or moderte nd were of short durtion. The proportions of ptients with VRC-prompted rsh (mesles-like, rubell-like, nd vricell-like) were comprble in both tretment groups, with no sttisticlly significnt differences observed. Mumps-like symptoms were lso prompted for on the VRC, lthough none were reported. For both tretment groups, the percentge of ptients who reported mesles-like, rubell-like, nd vricell-like rsh ws 6.4%, 1.2%, nd 3.0%, respectively. Immunogenicity Response rtes nd GMTs 6 weeks fter vccintion for mesles, mumps, rubell, nd vricell re shown in Tble 3. For both the refrigertor-stble nd frozen formultions of ProQud, the response rtes for mesles, mumps, nd rubell were 97.7% nd the percentge of ptients who hd bseline VZV ntibody titer 1.25 gpelisa U/mL nd chieved postvccintion VZV ntibody titer 5 gpelisa U/mL ws 88.8%. Becuse the lower bound of the 95% CI on the difference in response rtes between tretment groups ws 5 percentge points for mesles, mumps, nd rubell nd 10 percentge points for VZV, the response rtes to ech vccine ntigen in ptients who received the refrigertor-stble formultion of ProQud were considered similr to the frozen formultion. The proportion of ptients who hd bseline VZV titer 1.25 gpelisa U/mL nd chieved postvccintion VZV titer 1.25 gpelisa U/mL ws 98.9% for those who received the refrigertor-stble formultion of ProQud nd 97.9% for those who received the frozen formultion of ProQud (dt not shown). The response rtes tht were induced by the refrigertor-stble formultion of ProQud were found to be cceptble becuse the lower bound of the 95% CIs ws 90% for mesles, mumps, nd rubell, nd the percentge of ptients with postvccintion VZV titer 5 gpelisa U/mL ws 76%. Postvccintion GMTs were numericlly slightly higher in ptients who received the refrigertor-stble formultion of ProQud; however, the difference ws sttisticlly 1.5-fold between the formultions for ech vccine ntigen. Becuse the difference in GMTs ws 1.5-fold, the refrigertor-stble formultion of Pro- Qud ws considered similr to the frozen formultion. Success of the tril required tht the sttisticl nlysis show tht the refrigertor-stble formultion induced both response rtes nd GMTs tht were noninferior nd tht the response rtes were entirely bove the prespecified criteri (90% for mesles, mumps, nd rubell nd 76% [ 5 gpelisa U/mL] for vricell). DISCUSSION The refrigertor-stble formultion of ProQud ws highly immunogenic in 12- to 23-month-old children nd ws generlly well tolerted. No vccine-relted serious dverse experiences were reported, nd there were no cliniclly significnt differences in injection-site nd systemic dverse experiences between the 2 formultions. These results were generlly comprble to those reported in erlier trils with the frozen formultion, 10,11 except for the rtes of elevted temperture ( 102 F [ 38.9 C], orl equivlent), which were lower in this study. The lower rtes were most likely ttributed to chnge in dt collection methods in this study, including confirmtion of elevted xillry tempertures by the rectl method nd exclusion of qulittive reports of wrm to touch s tempertures 102 F ( 38.9 C). One limittion of this study ws tht the number of ptients ws not dequte to detect rre dverse experiences tht occurred t rte of 1 per 10 000 or less. TABLE 3 Mesles, Mumps, Rubell, nd VZV Response Rtes nd GMTs 6 Weeks After Vccintion Antigen (Assy) Prmeter ProQud Refrigertor-Stble (N 1006) Frozen (N 513) n Observed 95% CI n Observed 95% CI Response Response Mesles (ELISA) % 255 miu/ml 879 99.1% (871/879) 98.2% 99.6% 452 98.5% (445/452) 96.8% 99.4% GMT 2416 2298 2539 2399 2230 2581 Mumps (ELISA) % 10 ntibody U 883 97.7% (863/883) 96.5% 98.6% 447 98.0% (438/447) 96.2% 99.1% GMT 119 112 126 116 107 127 Rubell (ELISA) % 10 IU/mL 908 99.6% (904/908) 98.9% 99.9% 464 99.6% (462/464) 98.5% 99.9% GMT 97 92 102 94 87 101 Vricell (gpelisa) % 5 gpelisa U/mL 839 90.1% (756/839) 87.9% 92.0% 430 88.8% (382/430) 85.5% 91.7% GMT 12.2 11.6 12.9 11.8 11.0 12.8 N indictes number of ptients vccinted in ech tretment group; n, number of ptients with mesles ntibody titers 255 miu/ml, mumps ntibody titers 10 ELISA ntibody U, rubell ntibody titers 10 IU/mL, or VZV ntibody titers 1.25 gpelisa U/mL t bseline nd with postvccintion serology contributing to the per-protocol nlysis. GMTs for mesles, mumps, nd rubell hve been rounded to the nerest whole number. e1303
Such rre dverse experiences my be studied best in routine postlicensure surveillnce. Long-term, postlicensure, pssive surveillnce lredy provides extensive sfety experience for the components of ProQud (M- M-RII nd Vrivx). In recent yers, the recommended immuniztion schedule for children in the United Sttes hs become incresingly complex, with children receiving 20 or more injections in their first 18 months of life. The use of combintion vccines, such s ProQud, is n effective wy to overcome helth cre provider nd prentl concerns with multiple injections. In ddition, combintion vccines my improve the timely dministrtion of vccines, increse vccintion coverge rtes, reduce costs, nd llow for the ddition of new vccines into the routine immuniztion schedule. 9,20 Frozen vccines dd complexity to storge nd hndling in vrious settings. ProQud is currently vilble only s frozen formultion, nd the need to store it in the freezer limits its utility outside the United Sttes. 21 World Helth Orgniztion guidelines for countries tht re considering the implementtion of new vccine tht is intended for lrge-scle public helth use mndte tht the bility to overcome technicl limittions such s vccine storge temperture nd physicl storge cpcity be considered. 20,22 For mny developing nd remote res of the world, successful implementtion of vccine necessittes use of product tht does not require frozen storge. 23,24 Accordingly, vccines, with the exception of orl polio vccine, tht re supplied s prt of the World Helth Orgniztion sponsored Expnded Progrm on Immuniztion re recommended to be thermostble t refrigerted tempertures through the cold chin, originting with the mnufcturer nd ending with either regionl/district vccine stores or locl helth/dily use centers. 25,26 Avilbility of the refrigertor-stble formultion of ProQud, especilly where the vccine distribution infrstructure is not sufficient to mnge frozen vccine storge nd hndling, will further id the reduction of mesles, mumps, nd rubell diseses nd significntly decrese the incidence of vricell disese in countries other thn the United Sttes by fcilitting the ese of routine immuniztion ginst vricell. CONCLUSIONS Adopting this refrigertor-stble formultion of ProQud will lessen the burden of distribution nd storge on peditric prctices, increse the ese of vccine dministrtion, nd llow dditionl globl expnsion of current recommendtions throughout the world. This combintion vccine with its improved storge conditions my lso replce ny seprte dose of M-M-RII nd Vrivx for immuniztion ginst mesles, mumps, rubell, nd vricell. The refrigertor-stble formultion of ProQud would be expected to sustin lredy high globl vccintion rtes ginst mesles, mumps, nd rubell nd increse vccintion rtes ginst vricell. ACKNOWLEDGMENTS Members of the Refrigertor-Stble Formultion Study Group for ProQud include Wilson P. Andrews, MD, Jerry C. Bernstein, MD, Joseph Bertino, PhrmD, Steven B. Blck, MD, Stnley L. Block, MD, Louis Brine, MD, Kevin Browngoehl, MD, Rlph M. Conti, MD, Mtthew Cox, MD, Robert Drcker, MD, Crl-Erik Flodmrk, MD, Michel Gerber, MD, Gregory C. Gry, MD, J. Rndy Hedgepeth, MD, Hrry Keyserling, MD, Pul Lei, MD, Michel Levin, MD, Crl Lindgren, MD, Stephen Luber, MD, Edgrdo Mlcmn, MD, Colin Mrchnt, MD, Michelle Ogle, MD, Keith S. Reisinger, MD, Lrs Rombo, MD, Shelly D. Senders, MD, Julie Sheprd, MD, Dougls Short, MD, Mlcolm Sperling, MD, Robert Stcks, MD, Jmes Troutmn, MD, nd Jerry D. Twiggs, MD. We cknowledge the housestff, fculty, nurses, nd dministrtive stff t ech prticipting institution for prticiption nd support of this study. The editoril ssistnce nd meticulous ttention to detil of Alyss Scott is pprecited. We thnk the children nd their fmilies for prticiption in this reserch project. REFERENCES 1. Böttiger M, Christenson B, Romnus V, Trnger J, Strndell A. Swedish experience of two dose vccintion progrmme iming t eliminting mesles, mumps, nd rubell. Br Med J (Clin Res Ed). 1987;295:1264 1267 2. Centers for Disese Control nd Prevention. Summry of notifible diseses: United Sttes, 1998. MMWR Morb Mortl Wkly Rep. 1999;47:ii 92 3. Centers for Disese Control nd Prevention. Epidemiology nd Prevention of Vccine-Preventble Diseses. 9th ed. Atlnt, GA: Centers for Disese Control nd Prevention; 2006:125 170 4. Peltol H, Dvidkin I, Punio M, Vlle M, Leinikki P, Heinonen OP. Mumps nd rubell eliminted from Finlnd. JAMA. 2000; 284:2643 2647 5. World Helth Orgniztion Vccines nd Biologicls. WHO Vccine-Preventble Diseses: Monitoring System 2003 Globl Summry. Genev, Switzerlnd: World Helth Orgniztion; 2003 6. Centers for Disese Control nd Prevention. Ntionl, stte, nd urbn re vccintion coverge mong children ged 19 35 months: United Sttes, 2004. MMWR Morb Mortl Wkly Rep. 2005;54:717 721 7. Sewrd JF, Wtson BM, Peterson CL, et l. Vricell disese fter introduction of vricell vccine in the United Sttes, 1995 2000. JAMA. 2002;287:606 611 8. Centers for Disese Control nd Prevention. Decline in nnul incidence of vricell: selected sttes, 1990 2001. MMWR Morb Mortl Wkly Rep. 2003;52:884 885 9. Centers for Disese Control nd Prevention. Combintion vccines for childhood immuniztion. MMWR Recomm Rep. 1999; 48(RR-5):1 14 10. Shinefield H, Blck S, Digilio L, et l. Evlution of qudrivlent mesles, mumps, rubell nd vricell vccine in helthy children. Peditr Infect Dis J. 2005;24:665 669 e1304 BERNSTEIN et l
11. Shinefield H, Willims W, Mrchnt C, et l. Dose-response of qudrivlent mesles, mumps, rubell nd vricell vccine in helthy children. Peditr Infect Dis J. 2005;24:670 675 12. Mendez R, Henderson F, Reisinger K, et l. Immunogenicity nd sfety of process upgrde vricell vccine (PUVV) with new stbilizer s compred to PUVV with current stbilizer when dministered concomitntly with M-M-RII in helthy children. Presented t the 22nd nnul meeting of the Europen Society for Peditric Infectious Diseses; My 26 28, 2004; Tmpere, Finlnd 13. Bell KN, Hogue CJ, Mnning C, Kendl A. Risk fctors for improper vccine storge nd hndling in privte provider offices. Peditrics. 2001;107(6). Avilble t: www. peditrics.org/cgi/content/full/107/6/e100 14. Keller PM, Lonergn K, Neff BJ, Morton DA, Ellis RW. Purifiction of individul vricell-zoster virus (VZV) glycoproteins gpi, gpii, nd gpiii nd their use in ELISA for detection of VZV glycoprotein-specific ntibodies. J Virol Methods. 1986;14: 177 188 15. Wsmuth EH, Miller WJ. Sensitive enzyme-linked immunosorbent ssy for ntibody to vricell-zoster virus using purified VZV glycoprotein ntigen. J Med Virol. 1990;32: 189 193 16. Provost PJ, Krh DL, Kuter BJ, et l. Antibody ssys suitble for ssessing immune responses to live vricell vccine. Vccine. 1991;9:111 116 17. White CJ, Kuter BJ, Ngi A, et l. Modified cses of chickenpox fter vricell vccintion: correltion of protection with ntibody response. Peditr Infect Dis J. 1992;11:19 23 18. Li S, Chn I, Mtthews H, et l. Inverse reltionship between six week postvccintion vricell ntibody response to vccine nd likelihood of long term brekthrough infection. Peditr Infect Dis J. 2002;21:337 342 19. Miettinen O, Nurminen M. Comprtive nlysis of two rtes. Stt Med. 1985;4:213 226 20. World Helth Orgniztion. Immuniztion Focus of Western Pcific Regionl Office: Assessing New Vccines for Ntionl Immuniztion Progrmmes A Frmework to Assist Decision Mkers. Genev, Switzerlnd: World Helth Orgniztion; 2000 21. Centers for Disese Control nd Prevention. Notice to reders: guidelines for mintining nd mnging the vccine cold chin. MMWR Morb Mortl Wkly Rep. 2003;52:1023 1025 22. World Helth Orgniztion. Globl Progrmme for Vccines nd Immuniztion (GPV). The WHO position pper on Hemophilus influenze type b conjugte vccines. Wkly Epidemiol Rec. 1998;10:64 71 23. Heymnn DL, Smith EL, Nkno JH, Jto JG, Mrtin GE, Mben GK. Further field testing of the more het-stble mesles vccine in Cmeroon. Br Med J (Clin Res Ed). 1982;285: 531 533 24. Glzk A, Milstien J, Zffrn M. Thermostbility of Vccines: Globl Progrmme for Vccines nd Immuniztion (GPV). Genev, Switzerlnd: World Helth Orgniztion; 1998 25. World Helth Orgniztion. Globl Progrmme for Vccines nd Immuniztion (GPV): Sfe Vccine Hndling, Cold Chin nd Immuniztions A Mnul for the Newly Independent Sttes. Genev, Switzerlnd: World Helth Orgniztion; 1998 26. World Helth Orgniztion, Deprtment of Vccines nd Biologicls. Guidelines for Estblishing or Improving Primry nd Intermedite Vccine Stores. Genev, Switzerlnd: World Helth Orgniztion; 2002 e1305