Pre ven tion of Her pes Genitalis by the Bul gar ian Vac cine F.HSV-2 V (PRK): Pre lim i nary Clin i cal Ev i dence
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1 41(4): ,2000 BASIC SCIENCES Pre ven tion of Her pes Genitalis by the Bul gar ian Vac cine F.HSV-2 V (PRK): Pre lim i nary Clin i cal Ev i dence Gordon RB Skin ner, Ju dith A Davies, Stefan Dundarov 1, Pe ter Andonov 1 Vac cine Re search Trust, Moseley, Bir ming ham, UK; and 1 De part ment of Vi rol ogy, Na tional Cen ter of In fec tious and Par a sitic Dis eases (NCIPD), So fia, Bul garia Aim. To ex am ine the an ti genic prop er ties of the for ma lin-inactivated her pes sim plex vi rus type 2 (HSV-2) vi rus-particle vac - cine F.HSV-2 V (PRK), which has been used ther a peu ti cally in Bul garia for 30 years, and to make pre lim i nary as sess ment of its po ten tial pro tec tive ef fi cacy by a fol low-up of vac ci nated pa tients with her pes genitalis. Methods. Prop erties of the vac cine were ex am ined by stan dard im mu no log i cal lab o ra tory tests. Fifty-five pa tients at risk of her pes genitalis re ceived 2-4 vac ci na tions and were mon i tored dur ing a 6-year fol low-up. Results. The vac cine was an ti genic in lab o ra tory tests and ab sorbed neu tral iz ing an ti body from hyperimmune rab bit se rum against her pes sim plex vi rus type 1 (HSV-1). In vac ci nated pa tients, there was an over all con trac tion rate of her pes genitalis of 5.4%. There was no ev i dence of sig nif i cant lo cal or gen er al ized ad verse ef fects from vaccination. Conclusion. Bul gar ian vac cine F.HSV-2 V (PRK) may have pro tec tive ef fi cacy, which, in as so ci a tion with its ap par ent safety from our find ings and from its clin i cal use for over 30 years in Bul garia, sug gests that it should be scru ti nized by a for mal clin i - cal trial. Key words: ad ju vants, im mu no log i cal; Bul garia; her pes genitalis; her pes labialis; HIV; sex be hav i or; sex u ally trans mit ted dis eases; vac cine Her pes vi rus in fec tions con tinue to be a ma jor prob - lem, with rates of con trac tion of in fec tion ris ing alarm - ingly in the past 20 years. A re cent re view by Kinghorn (1) in di cates that, while rates of other sex u ally trans mit - ted dis eases such as gon or rhea and syph i lis have de - clined, the in ci dence of her pes genitalis in the United King dom has in creased threefold. Cur rent pat terns of sex ual be hav ior sug gest that this trend will con tinue in the fore see able fu ture. Her pes genitalis can cause con - sid er able dis tress and de bil i ta tion and has been linked to sus cep ti bil ity to other in fec tions in par tic u lar the hu - man im mu no de fi ciency vi rus (HIV) with in volve ment in trans mis sion of HIV in fec tion (2,3), or di rectly in the pro gres sion of dis ease through, ac ti va tion of HIV tran - scrip tion (4). Med i ca tions such as Acyclovir or Valacyclovir have been only par tially suc cess ful in the treat ment of her pes sim plex in fec tion. Fur ther more, there is a pos si bil ity of the de vel op ment of drug- resistant strains and as so ci ated prob lems, i.e., sup pres sion of the host im mune system dur ing long term ther apy (5). Additionally, drug treat - ments seem un able to re duce con trac tion of in fec tion in part ners of asymp tom atic car ri ers who are not re ceiv ing drug treat ment. There are no re ports of pro tec tive ef fi - cacy in hu mans of any vac cines cur rently un der de vel op - ment. While there is a prog ress made in the search for an ef - fec tive and safe pre ven ta tive vac cine, suc cess ful tri als of the pro tec tive ef fi cacy of any vac cine cur rently un der de - vel op ment have not yet been re ported. The pre ven ta tive ef - fi cacy of Skin ner in ac ti vated intracellular vac cine, which has been in named pa tient us age in the United King dom for 2 de cades (6) and has un der gone pla cebo-controlled trial of therapeutic efficacy in the United States (7), has not yet been scru ti nized in pla cebo-controlled tri als due to the lack of fund ing. Sub unit glyco protein prep a ra tions and re com - bi nant or ge net i cally dis abled vi rus vac cines are cur rently un der go ing de vel op ment or trial (8-13). How ever, the pro - tective immunogenicity of sin gle glycoproteins ex tracted from vi rus-infected cells or pre pared by re com bi nant tech - nol ogy re mains un proved, as sug gested by the dis ap point - ing re sults with glyco protein D vac cine (14). It is also a con cern that live at ten u ated or dis abled vac cines may re
2 cover patho ge nic ity through re com bi na tion with wild type strains a mat ter of se ri ous im portance for a vi rus with po - tential to cause keratitis or encephalitis. It is imperative, therefore, not to forego the evaluation of all reasonable vac cine can di dates. We have eval u ated a vac cine, des ig nated as F.HSV-2 V (PRK), in ac cor dance with the no men cla ture we have used for our vac cines de vel oped in the UK dur - ing the pre vi ous two de cades (15-18). The vac cine is for - ma lin-inactivated (F) and pre pared from 5 strains ( V ) of HSV-2 iso lated from pri mary rab bit kid ney cells (PRK). Al though this vac cine has been in clin i cal prac tice for the ther a peu tic man age ment of her pes ophthalmicus in Bul - garia for 30 years (19-24), its pre ven ta tive ef fi cacy has never been in ves ti gated. We re port on the preliminary ev i dence of pre ven ta tive ef fi cacy in pa tients of pa tients with her pes genitalis. Ma te rials and Methods Vaccine The Bul gar ian vac cine is a for ma lin-inactivated vi rus par ti cle prep a ra tion ob tained from cel lu lar ex tracts of her pes sim plex vi rus (HSV-2)-in fected new born rab bit kid ney cells (NCIPD Dried Her pes vac cine type II, Na tional Cen ter of In fec tious and Par a sitic Dis eases, So fia, Bul garia). The vac cine vi rus strains in clude 5 field iso lates from pa tients with gen i tal her pes, leg le sions, and la bial ne crotic le - sions which were originally selected from 400 newly isolated strains with dif fer ent prop er ties for their immunogenicity and ab sence of oncogenic po ten tial or ef fect on chromosoms (19-21,23,25). Af ter iso la tion, these strains were lyophilized af ter 2-4 pas sages. Vac cines used in this study were pre pared from these pri mary pas sages, and the prep a ra tion has been de scribed else where (21,25). Briefly, the 5 vi rus strains were used to infect roller cultures of cells ob tained by trypsinization of kid neys from 10 to 14-day-old rab bits bred from con tin u ally mon i tored stock. The cells were har vested af ter the de vel - op ment of 90% vi rus cytopathic ef fect, dis rupted by ul tra sonic vi bra - tion, and cen tri fuged to re move the cell de bris. The supernatant was first treated with 0.02% form al de hyde for 24 h at 37 C, then for 72 h at 4 C to in ac ti vate the vi rus, and fi nally di a lyzed against 1L phos - phate buf fered sa line (PBS, Oxoid Chem i cals Ltd., Basingstoke, UK) for 24 h at 4 C to re move for ma lin. The vac cine was rou tinely tested in Bul garia for in fec tious vi rus by 3 pas sages in dip loid hu man em - bryo lung cells and for immunogenicity and toxicity in mice and guinea pigs. The qual ity of the vac cine was con trolled and ap proved by the National In sti tute of Drugs, Bul garia. No side ef fects have been ob served af ter the use of vac cine in more than 15,000 pa tients over 17 years of re corded ob ser va tions in Bul garia (23). Each vac cine dose (Batch ) con tained at least 10 8 vi ral par ti cles. Lab o ra tory Anal y sis of the Vac cine An ti ge nic ity of the vac cine was tested in our lab o ra tory in the UK by polyacrylamide gel electrophoresis, immunodiffusion, ELISA, radioimmunoassay, and ab sorp tion of neu tral iz ing an ti body from hyperimmune an ti sera against HSV-1. Un less oth er wise stated, lyophilized vac cine was re con sti tuted in 0.5 ml H 2 O. In cer tain tests, Bul gar ian HSV-2 vac cine F.HSV-2 V [PRK] (Batch ) was com - pared against the Skin ner vac cine NFU.Ac.HSV-1[S - MRC-5] and Bul gar ian HSV-1 vac cine F.HSV-1 V [PRK] (Batch ). Cells and Vi ruses for Lab o ra tory Tests Baby ham ster kid ney cells (BHK-21, clone 13) were main - tained in Ea gle s min i mum es sen tial me dium, Glas gow mod i fi ca tion, sup ple mented with 10% tryptose phos phate broth and 10% new born calf se rum (ETC, Life Tech nol ogies Ltd, Pais ley, UK). Her pes sim - plex vi rus type 1 (strain Troisbel, iso lated in our lab o ra tory) and her - pes sim plex vi rus type 2 strain 3345 (26,27) were used for neu tral iza - tion ex per i ments and main tained in BHK-21 cells. An ti sera for Lab o ra tory Tests An ti serum to HSV-1 was pre pared in rab bits by 10 sub cu ta ne - ous inoculations of the formaldehyde-inactivated extract of HSV-1-infected rab bit kid ney cells. Alu minium hy drox ide was used as adjuvant in all cases and se rum was col lected 10 days af ter each in - oc u la tion. An ti serum to HSV-1 gd (Band II) was pre pared as for HSV-1 using HSV-1 gd (Band II) protein eluted from polyacrylamide gels (28). Polyacrylamide Gel Elec tro pho re sis (PAGE) An ti gens were dis solved in dis rup tion mix ture con tain ing 2% w/v SDS and 5% v/v mercaptoethanol in 0.05 mol/l TRIS buffer (BDH Ltd, Poole, England), heated to 90 C for 10 min and electrophoresed ac cord ing to a stan dard method. En zyme-linked Immunosorbent As say (ELISA) We titrated antigenic activity using an indirect solid phase immunoassay system. Antigens were coated overnight onto microtiter plates in 0.05 mol/l car bon ate buffer (BDH Ltd) ph 9.6 at 4 C, ex cess an ti gen re moved, and bound an ti gen in ac ti vated with 0.05% glutaraldehyde (Sigma Chem i cal Co., Poole, UK). Plates were washed five times in PBS (Oxoid) containing 0.1% Tween 20 (Sigma) and blocked for 1 h at 37 C in PBS/Tween 20 (Sigma) con - tain ing 1% Mar vel milk pow der (Cad bury Schweppes Ltd., Bir ming - ham, UK). Se rum di luted in PBS/Tween/Mar vel was added for 1 h at 37 C and then re moved. The plates were washed as de scribed and in - cu bated with peroxidase-conjugated sheep anti-species IgG di luted 1:1,000 or 1:2,000 in PBS/Tween/Mar vel for 1 h at 37 C. The plates were washed again and the re ac tion was de vel oped with 1 mmol/l enzyme substrate 2,2 -azino-di-3--ethylbenzanthiazoline-6-sulphonic acid (ABTS) in 0.1 mol/l ci trate phos - phate buffer ph 5.0 ac ti vated by H 2 O 2 (Sigma). Radioimmunoassay Antigens were diluted in PBS and coated overnight onto round-bottomed flex i ble microtiter trays (Flow Labs, Mclean, VA, USA) at 4 C. An ti gen was re moved, trays were washed five times with PBS and non-specific sites blocked with 50% new born calf se - rum in PBS at 37 C for 1 h. then, the trays were washed once in PBS and se rum di lu tions were added for 1 h at room tem per a ture. The se - rum was re moved, trays washed five times with PBS, and 131 I-labeled pro tein A added at 30,000-50,000 counts per min (cpm) per well. Af - ter in cu ba tion at 37 C for 1 h, the plate was washed and dried, cut into in di vid ual wells, and counted on a gamma coun ter. Ab sorp tion of Neu tral iza tion The abil ity of vac cine to ab sorb neu tral iz ing an ti body from hyperimmune se rum was ex am ined by in cu bat ing the vac cine or vi - rus in fected-cell an ti gen as a pos i tive con trol, with a 1/40 di lu tion of hyperimmune rab bit an ti serum against HSV-1 for 1 h at 37 C and a fur ther 24 h at 4 C. Be fore use, the vac cine was re con sti tuted in H 2 O at 0.2 ml per vial and di a lyzed in PBS at 4 C for 24 h to re move form al de hyde. The ab sorbed sera were then tested for vi rus neu tral iz - ing ability by incubating with HSV-1 or HSV-2 at 5x10 6 plaque-forming units (pfu)/ml fi nal con cen tra tion for 1 h at 25 C and ti trat ing re sid ual vi rus on BHK-21 cells by plaque as say (29). Clin i cal Study Fifty-five sub jects who did not have a his tory of clin i cal herpes genitalis, but whose reg u lar sex ual part ner had an un equiv o cal clin i - cal his tory of the dis ease, re ceived 1-4 vac ci na tions. There was no pro spec tive strat i fi ca tion as the study was de signed to fol low up a small rep re sen ta tive pop u la tion of pa tients who at tended a clin i cal practice in the United Kingdom and who were vaccinated on a named pa tient ba sis. None of the pa tients, all aged be tween 16 and 70 years, was immunosuppressed or re ceiv ing immunosuppressive drugs. None were preg nant, but a neg a tive preg nancy test was not re - quired as a con di tion of re ceiv ing the vac cine, and none of the fe male pa tients be came preg nant within the first year fol low ing vac ci na tion. Pa tients were not asked to adopt con tra cep tive or other bar rier meth - ods of dis ease pre ven tion than those usu ally ad vised in clin i cal prac - tice. There fore, the pa tients ex pe ri enced nor mal con di tions of ex po - sure to her pes genitalis and ap prox i mately 33% had a his tory of her - pes labialis. The de mo graphic fea tures of the pa tients are shown in Table 1; there were 26 men and 29 women of an av er age age of 31.8±1.9 years; 16 par tic i pants were mar ried and 37 were sin gle or re ported mar i tal dis so lu tion. Most par tic i pants were in higher so cial class as de fined by the Reg is trar Gen eral s scale, United King dom. The vac cine was mixed with 0.25 ml Alhydrogel adjuvant (30,31) in all but 5 cases, where adjuvant was not used but the vac cine was ad min is tered by sub cu ta ne ous in oc u la tion into the pos te rior as - pect of the up per arm at in ter vals of ap prox i mately 1 week. Four pa - tients were vac ci nated at 3-day in ter vals and 3 pa tients at 3-week in - ter vals. Each vac cine dose con tained at least 10 8 vi rus par ti cles, which 379
3 was the dose used in pre vi ous stud ies with her pes ophthalmicus in Bul garia (23,24). Pa tients were asked to make im me di ate con tact in the event of any sus pected out break of her pes genitalis and were fol lowed up by in ter view and phys i cal ex am i na tion at in ter vals of 3 months over the first year af ter vac ci na tion. There af ter, pa tients were fol lowed up by tele phone in ter view. Re sults Prop erties of Vac cine The pro tein com po si tion of the vac cine was ex am ined by polyacrylamide gel elec tro pho re sis (PAGE); there were polypeptides in molecular weight regions of ap prox i - mately kd, kd, and kd (data not shown). There were no immunoprecipitins on test ing with anti-hsv type 1 or type 2 hyperimmune rab bit sera, as ex - pected in a non-disrupted vi rus par ti cle vac cine. On test ing by ELISA against hyperimmune anti-hsv-1 se rum, an ti gen di lu tion end points of log and 1.8 were ob tained for the type 1 and type 2 vac - cines, re spec tively. End points of log and 2.8 were ob tained on test ing against anti-gd (Band II) serum. These val ues were slightly lower than those ob tained with the Skin ner her pes sim plex vaccine (32) against anti-hsv1 an ti serum, al though val ues against anti-gd (Band II) were com pa ra ble and pre sum ably re flected the rel a tive in crease in the pro por tion of glycoprotein D in a Table 1. Socio-demographic features of patients a Number of subjects 55 Number of men 26 Age (years) Range Mean±SD 31.8±1.3 Social class b A/B 32 C 17 D/F 3 Marital status Not married 37 Married 16 Unrecorded 2 Ethnic background White European 47 Asian 5 African Caribbean 1 Nationality UK 49 USA 4 Republic of Ireland 1 Australia 1 History herpes labialis Positive 19 Negative 34 Unknown 2 a Num bers do not to tal to 55 if the re quired in for ma tion was not known or not re corded for any of the pa tients. b Ac cord ing to the Reg is trar Gen eral s So cial Scale, 1990, for the UK ( ABC1 scale): A pro fes sional work ers (law yers, doc tors etc.), sci en - tists, man ag ers of large scale or gani sa tions; B shop keep ers, farm ers, teach ers, white-collar work ers; C 1) skilled man ual (i.e. hand) work ers high grade, e.g., mas ter build ers, car pen ters, shop as sis tants, nurses, 2) skilled man ual low grade. e.g., elec tri cians, plumb ers; D semi-skilled man ual, e.g., bus driv ers, lorry driv ers, fit ters; E un skilled man ual, e.g., gen eral la bour ers, bar men, por ters. vi rus par ti cle vac cine in com par i son with the Skin ner her pes vac cine (33) (Ta ble 2). On radioimmunoassay, when an ti sera were ti trated against un di luted vaccine, end point se rum di lu tions of log were ob tained for both vac cines. In ves ti ga tion of ab sorp tion of neu tral iz ing an ti body by vac cine an ti gen was ini tially com pli cated by virucidal ac tiv ity in the vac cine it self. This pre sum ably arose from form al de hyde, which was used to in ac ti vate the vi rus dur ing vac cine prep a ra tion and was re moved by di al y sis (Ta ble 3). Dialyzed vac cine ab sorbed neu tral iz ing ac tiv - ity from a rab bit hyperimmune anti-hsv-1 se rum, with de creases in neu tral iza tion lev els from log to 0.14 for HSV-1 and from log to less than 0.1 for HSV-2. These re duc tions in neu tral iza tion were com pa - ra ble to de creases in neu tral iza tion ob tained af ter the ab - sorp tion of an ti serum with di a lyzed in fected-cell ex tract con tain ing ap prox i mately 1x10 7 cells per ml (Ta ble 4). Clin i cal Study None of the 55 pa tients with drew from the study or had to be ex cluded. None of the 16 pa tients who re ceived 3 or 4 vac ci na tions con tracted clin i cal ev i dence of her - pes genitalis dur ing the 6-year fol low-up. Three of the 24 pa tients who re ceived 2 vac ci na tions one with out adjuvant con tracted her pes genitalis as well as 1 of the 15 pa tients who re ceived just 1 vac ci na tion with out adjuvant. Thus, only 4 out of 55 pa tients and only 2 of the 50 who were vac ci nated with adjuvant con tracted her pes genitalis, giv ing an over all rate of con trac tion of dis ease in vac ci nated pa tients of 7.2% (Ta ble 5). There was no ev i dence of gen eral or sig nif i cant lo - cal side ef fects dur ing 330 pa tient-years of the fol low-up. Pa tients who re ceived the vac cine with out adjuvant ex - pe ri enced a mi nor short-lived sting ing sen sa tion, which did not oc cur if the vac cine was given with the Alhydrogel adjuvant. Most pa tients de vel oped a granulomatous re ac tion at the vac ci na tion site, if vac ci - na tions were given with the adjuvant, but these re ac tions dis ap peared in most pa tients within 6 weeks and were not pres ent in any pa tient at one year af ter vac ci na tion. Dis cus sion This study has ex am ined the ef fi cacy of a whole vi - rus par ti cle vac cine in pa tients at risk of con tract ing her - pes vi rus in fec tion. The vac cine dem on strated an ti ge nic - ity in im mu no log i cal as says and by ab sorp tion of HSV-1 Table 2. Reactivity (Log 10 endpoint reactivity a ) of Bulgarian vaccine and Skinner vaccine by ELISA Bulgarian vaccine Skinner HSV Serum HSV Type 1 HSV Type 2 vaccine Anti HSV-1 1/ / Anti gd (Band II) 1/ / / a Re sults are ex pressed as end points of re ac tiv ity of a di lu tion se ries of the vaccine. 380
4 Table 3. Virucidal activity of vaccine before and after dialysis Table 4. Absorption of neutralization by dialyzed vaccine Log 10 reduction in virus titerb Serum absorbed with a HSV-1 HSV-2 Medium alone Dialyzed vaccine Type Type Dialyzed infected-cell antigen HSV-1 antigen 5x10 8 cells/ml x10 7 cells/ml x10 6 cells/ml HSV-2 antigen 5x10 8 cells/ml x10 7 cells/ml x10 6 cells/ml a Hyperimmune rab bit an ti serum against HSV-1 was di luted to 1/40 and ab sorbed with an equal vol ume of ei ther vac cine re con sti tuted in H 2 O at 0.2 ml per vial or vi rus in fected-cell an ti gen, for 1 h at 37ºC and a fur ther 24 h at 4ºC, be fore test ing for re sid ual vi rus-neutralizing abil ity. b Re sults are ex pressed as log 10 re duc tion in the vi rus ti ter fol low ing in cu - ba tion with ab sorbed sera for 1 h at room tem per a ture. and HSV-2 neu tral iz ing ac tiv ity from hyperimmune rab - bit se rum pre pared against HSV-1. The over all rate of dis ease con trac tion in vac ci nated pa tients was 7.2%, but only 4% in the vac ci nated with adjuvant. This rep re sents a mar gin ally higher fail ure rate than the 2% con trac tion rate in pa tients im mu nized with the Skin ner intracellular vac cine (6), where the ma jor ity of pa tients were vac ci nated with adjuvant. The higher Table 5. Contraction (No. of subjects) rate in vaccinated patients No. of vaccinations Total Receiving adjuvant Log 10 reduction in virus titer a Vaccine HSV-1 HSV-2 Non-dialyzed Type Type Dialyzed Type Type a Equal vol umes of a 1/10 di lu tion of vac cine which had been re con sti tuted in H 2 O at 0.5 ml per vial were in cu bated with vi rus sus pen sion con tain ing 3.6x10 6 pfu per ml at room tem per a ture for 1 h. Re sults are ex pressed as log 10 re duc tion in the vi rus ti ter fol low ing in cu ba tion. Contraction infection in vaccinated with without adjuvant adjuvant Total con trac tion rate in pa tients vac ci nated with out adjuvant may be sur pris ing in the light of stud ies by Dundarov et al (22-24), but hardly in di cates an es sen tial re quire ment for adjuvant, as there were too few pa tients in this group for proper sta tis ti cal eval u a tion. How ever, pend ing fur - ther ev i dence, there seems little reason to es chew Alhydrogel, which is safe, eco nom i cal, and has stood the test of time (30,31). A the o ret i cal prob lem with vac ci nated pa tients who have had no clin i cal ev i dence of dis ease is that they may al ready be asymptomatically in fected and that sub se - quent clin i cal re cur rences will be dif fi cult to dis tin guish from de novo con trac tion of dis ease. This prob lem did not seem to af fect the Skin ner study (6) and there is, in fact, no def i nite ev i dence that the asymp tom atic con trac - tion of the dis ease will sub se quently re sult in overt clin i - cal dis ease, nor that it is a sig nif i cant fac tor in the trans - mis sion of this vi rus. The vac ci nated con sort would pre - sum ably pre fer to not have re cur rences and there would nor mally be less vi rus ex cre tion in the asymp tom atic sit - u a tion than dur ing re cur rences. How ever, this im por tant is sue could be re solved only by daily vi rus iso la tion, which, al though te dious and time-consuming, is nev er - the less a fea si ble pro ject. This is an open study and raises the crit i cal ques tion of the rate of in fec tion in a com pa ra ble pop u la tion of pa - tients at risk. While there is a pau city of data on this, a study by Mertz et al (34) has in di cated a con trac tion rate of ap prox i mately 12% within one year, 29% within 16 months, and 82% in 3-7 years in pa tients at risk of in fec - tion. These rates are not dis sim i lar from an ear lier study that re ported a con trac tion rate of 29% in one year of fol - low up, al though this in for ma tion was based on a rather small sam ple and one of the in dex cases was re spon si ble for in fect ing 4 of the pa tients at risk (33). Thus, the over - all con trac tion rate with the Bul gar ian vac cine 5.4% in the 6 years of this study would seem to com pare fa vor - ably with the rate in un vac ci nated pa tients over sim i lar pe ri ods of fol low up. There was no ev i dence of side ef fects in any of the vac ci nated pa tients dur ing the fol low up. This raises the con tro ver sial ques tion of the im por tance of vi rus. i.e., cel lu lar DNA in vac cine prep a ra tions. Whereas it would seem gen er ally pru dent to min i mize vi rus DNA con tent in a po ten tial vac cine, and per haps more so if there is ev i - dence that this vi rus may have oncogenic po ten tial (35-37), there seems to be lit tle ev i dence to sug gest that the in oc u la tion of killed whole-virus vac cines has been ac com pa nied by sig nif i cant side ef fects (38). In deed, there is no clear as so ci a tion be tween her pes labialis and car ci noma in that site, where the sub ject has pre sum ably re ceived reg u lar in oc u la tions of fresh na tive vi rus DNA over many years. In ad di tion, an ti gen-encoding genes within plasmid DNA are now used in vac cine de vel op - ment (39-41), whereas whole-inactivated and live- atten - uated vac cines against HIV have been ac cepted for hu - man clin i cal tri als (42-45). There fore, there may be good rea sons to re con sider our views on the sig nif i cance of vi - rus DNA in vac cine prep a ra tions. This study has sug gested that Bul gar ian vac cine F.HSV-2 V (PRK), which has been used to date only for ther a peu tic pur poses, may have pro tec tive efficacy, which, in as so ci a tion with its ap par ent safety from both 381
5 the pres ent study and its clin i cal use in over 10,000 pa - tients over 30 years in Bul garia, pro vides an ar gu ment that the pre ven ta tive ef fi cacy of this vac cine should be sub jected to the scru tiny of for mal clin i cal trial. Acknowledgment We thank Dr S. Dundarov, De part ment of Vi rol ogy, Na tional Cen ter of In fec tious and Par a sitic Dis eases (NCIPD), So fia, Bul garia, for sup ply ing us with the vac cine. The Vac cine Re search Trust, Bir - ming ham, UK, fi nan cially sup ported the study. Ref er ences 1 Kinghorn GR. Lim it ing the spread of gen i tal her pes. Scand J In fect Dis Suppl 1996;100: Holmberg SD, Stew art JA, Gerber AR, Byer RH, Lee FK, O Mal ley PM, et al. Prior her pes sim plex vi rus type 2 in - fection as a risk factor for HIV infection. JAMA 1988;259: Hook EW 3d, Can non RO, Nahmias AJ, Lee FF, Camp bell CH Jr, Glaser D, et al. Her pes sim plex vi rus in fec tion as a risk fac tor for hu man im mu no de fi ciency vi rus in fec tion in het ero sex u als. J In fect Dis 1992;165: Mosca JD, Bednarik DP, Raj NB, Rosen CA, Sodroski JG, Haseltine WA, et al. Ac ti va tion of hu man im mu no de fi - ciency vi rus by herpesvirus in fec tion: iden ti fi ca tion of a re - gion within the long terminal re peat that responds to a trans-acting fac tor en coded by her pes sim plex vi rus. Proc Natl Acad Sci USA 1987; 84: Erlich KS, Hauer L, Mills J. Ef fects of long-term Acyclovir chemosuppression on se rum IgG antibody to her pes sim plex vi rus. J Med Virol 1988;26: Skinner GR, Fink C, Melling J, Wiblin C, Thornton B, Hallworth J, et al. Re port of twelve years ex pe ri ence in open study of Skin ner her pes sim plex vac cine to wards pre - vention of her pes genitalis. Med Microbiol Immunol 1992;180: Skinner GR, Turyk ME, Benson CA, Wilbanks GD, Heseltine P, Galpin J, et al. The ef fi cacy and safety of Skin - ner her pes sim plex vac cine to wards mod u la tion of her pes genitalis: report of a pro spec tive double-blind pla - cebo-controlled trial. Med Microbiol Immunol 1997;186: Burke RL. De vel op ment of her pes sim plex vi rus sub unit glycoprotein vac cine for pro phy lac tic and ther a peu tic use. Rev In fect Dis 1991;13:S Nakao M, Hazama M, Mayumi-Aono A, Hinuma S, Fujisawa Y. Immunotherapy of acute and re cur rent her pes sim plex vi rus type 2 in fec tion with an adjuvant-free form of re com bi nant glycoprotein. J In fect Dis 1994;169: Gallichan WS, Johnson DC, Graham FL, Rosenthal KL. Mucosal im mu nity and pro tec tion af ter intranasal im mu ni za - tion with re com bi nant adenovirus ex press ing her pes sim plex vi rus glycoprotein-b. J In fect Dis 1993;168: Farrell JE, McLean CS, Harley C, Efstathiou S, Inglis S, Minson AC. Vac cine po ten tial of a her pes sim plex vi rus type/mu tant with an es sen tial glycoprotein de leted. J Virol 1994;68: McLean CS, Erturk M, Jennings R, Ni Challanian D, Minson AC, Duncan I, et al. Pro tec tive vac ci na tion against pri mary and re cur rent dis ease caused by her pes sim plex vi - rus [HSV] type 2 us ing a ge net i cally dis abled HSV-1. J In - fect Dis 1994;170: Brehm MA, Bonneau RH, Knipe DM, Tevethia SS. Im mu - ni za tion with a rep li ca tion-deficient mu tant of her pes sim - plex vi rus type 1 (HSV-1) in duces a CD8 cytotoxic lym - pho cyte re sponse and con fers a level of pro tec tion com pa - ra ble to that of wild-type HSV-1. J Virol 1997;71: Mertz GH, Ashley R, Burk RL, Benedetti J, Critchlow C, Jones CC, et al. Dou ble-blind, pla cebo-controlled trial of HSV type 2 glycoprotein vac cine in per sons at high risk for gen i tal her pes in fec tions. J In fect Dis 1990;161: Skin ner GR, Wood man C, Hartley C, Buchan A, Fuller A, Wiblin C, et al. Early ex pe ri ence with antigenoid vac - cine Ac NFU1(S - ) MRC to wards pre ven tion or mod i fi ca - tion of her pes genitalis. Dev Biol Stand 1982;52: Skin ner GR, Wood man CB, Hartley CE, Buchan A, Fuller A, Durham J, et al. Prep a ra tion and immu nogenicity of vac cine Ac NFU1(S - ) MRC to wards the pre ven tion of her - pes genitalis. Br J Vener Dis 1982; 58: Skin ner GR, Buchan A, Davies J, Dur ham J, Castrucci G. A vi rus-particle vac cine pre pared from bo vine mammillitis vi rus against her pes genitalis. Comp Immunol Microbiol In fect Dis 1991;14: Billstrom MA, Davies JA, Buchan A, Skin ner GR. De vel - op ment of sub unit prep a ra tions of cyto mega lovirus an ti gen by aque ous extraction for immunization against cytomegalovirus in fec tion. Intervirology 1993;36: Dundarov S, Andonov P, Bakalov B, Peeva Z. An ti genic dif fer ences be tween strains of her pes sim plex vi rus. Probl In fect Parasit Dis 1975;3: Andonov P, Dundarov S, Bakalov R. Prep a ra tion and pro - phy lac tic-therapeutical ef fect of Bul gar ian in ac ti vated polyvalent Her pes vac cines. Acta Med Bulg 1979;6: Dundarov S, Andonov P, Bakalov B. Char ac teri sa tion of herpes sim plex vi rus strains isolated from pa tients with var i ous dis eases. Arch Virol 1980;63: Dundarov S, Andonov P, Bakalov B, Nechev K, Tomov C. Immunotherapy with in ac ti vated poly valent vac cines. Dev Biol Stand 1982;52: Dundarov S, Andonov P. Sev en teen years of ap pli ca tion of her pes vac cines in Bul garia. Acta Virol 1994;38: Dundarov S, Kawaklova L, Markova R, Tateojyan D, Valkova B, Simeonova M, et al. Clin i cal and im mu no log i - cal ef fec tive ness of dif fer ent types of her pes vac cines pro - duced in Bul garia; study on vol un teers. VIII In ter na tional Congress on In fec tious Dis eases; 1988 May 15-19; Boston, USA. ABS Andonov P, Dundarov S, Bakalov R. De sign of in ac ti vated polyvalent antiherpes vac cines [in Bul gar ian] Vopr Virusol 1979;(6): Skin ner GR, Thouless ME, Trueman S, Ed wards J, Gibbs AJ. Serological re lat ed ness of her pes simplex viruses; type-specificity of an ti body re sponse. Im mu nol ogy 1976;31: Birch J, Fink CG, Skin ner GR, Thomas GH, Jor dan JA. Replication of type 2 her pes sim plex vi rus in hu man endocervical tis sue in or gan cul ture. Br J Exp Pathol 1976;57: Wat son DH, Wildy P. The prep a ra tion of mono pre ci pitin antisera to her pes vi rus specific an ti gens. J Gen Virol 1969;4: Rus sel WC. A sen si tive and pre cise plaque as say for her - pes vi rus. Na ture 1962;195: White JL, Schlageter EA. Diptheria toxoid. Com para tive immunizing value with and with out alum, as in di cated by Schick test. J Am Med Assoc 1934;102: Gupta RK, Relyveld EH, Lindblad EB, Bizzini B, Ben-Efraim S, Gupta CK. Adjuvants a bal ance be tween tox ic ity and adjuvanticity. Vac cine 1993;11: Skin ner GRB, Wood man KCBJ, Hartley CE, Buchan A, Fuller A, Dur ham J, et al. The preparation and immu - nogenicity of vac cine Ac.NFU1(S - ) MRC5 to wards pre - 382
6 ven tion of her pes genitalis in hu man sub jects. Br J Vener Dis 1982;58: Skinner GR, Fink CG, Cowan M, Buchan A, Fuller A, Hartley CE, et al. Fol low-up re port on 50 sub jects vac ci - nated against her pes genitalis with Skin ner vac cine. Med Microbiol Immunol 1987;176: Mertz GJ, Coombs RW, Ashley R, Jourden J, Remington M, Win ter C, et al. Trans mis sion of gen i tal her pes in cou - ples with one symp tom atic and one asymp tom atic part ner: A pro spec tive study. J In fect Dis 1988;157: Andonov P, Bakalov B, Dundarov S, Uzunov P, Karchev T, Karabasheva V, et al. A study on the pos si ble oncogenic prop er ties of human her pes vi ruses [in Bul gar ian]. Epidemiologija, Microbiologija, In fek tiozni Bolesti 1975;2: Wilbanks GD. The role of her pes vi rus in can cer of the cer - vix. Obstet Gynecol Annu 1976;5: Jones C. Cer vi cal can cer: is her pes sim plex vi rus type II a co fac tor? Clin Microbiol Rev 1995;8: Drucker J. In ac ti vated vac cines: char ac ter is tics and prin ci ples of use [in French]. Rev Prat 1995;45: Mor G. Plasmid DNA: a new era in vaccinology. Biochem Pharmacol 1998;55: Hoffman SL, Doo lan DL, Sedegah M, Wang R, Scheller LF, Kumar A, et al. To ward clin i cal tri als of DNA vac cines against ma laria. Immunol Cell Biol 1997;75: MacGregor RR, Boyer JD, Ugen KE, Lacy KE, Gluck man SJ, Bagarazzi ML, et al. First hu man trial of a DNA-based vaccine for treat ment of hu man im mu no de fi ciency vi rus type 1 infection: safety and host response. J In fect Dis 1998;178: Zagury D, Ber nard J, Halbreich A, Bizzini B, Carelli C, Achour A, et al. One year fol low-up of vac cine ther apy in HIV-infected im mune-deficient in di vid u als: a new strat - egy. J Acquir Im mune Defic Syndr 1992;5: Dan iel M, Kirchoff E, Czajak SC, Sehgal PK, Dero siers RC. Pro tec tive ef fects of a live at ten u ated SIV vaccine with a de le tion in the nef gene. Sci ence 1992;258: Shibata R, Siemon C, Czajak SC, Derosiers RC, Mar tin M. Live, at ten u ated sim ian im mu no de fi ciency vi rus vac cines elicit po tent re sis tance against a chal lenge with a hu man im mu no de fi ciency virus type 1 chi me ric virus. J Virol 1992;71: Co hen J. Novel cam paign to test live HIV vac cine. Sci ence 1997;277:1035. Re ceived: April 5, 2000 Ac cepted: Sep tem ber 4, 2000 Cor re spon dence to: Ju dith Davies Vac cine Re search Trust 22 Alcester Road, Moseley Bir ming ham B13 8BE, UK vaccine.trust@fdn.co.uka 383
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