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Letters
Current Status of Smallpox Vaccine
To the Editor: The possible use of smallpox virus as a weapon by terrorists has
stimulated growing international concern and led to a recent review by the World Health
Organization of the global availability of smallpox vaccine. This review found
approximately 60 million doses worldwide, with little current vaccine manufacture,
although limited vaccine seed remains available (1). Ongoing discussions in the United
States suggest that the national stockpile should contain at least 40 million doses to be
held in reserve for emergency use, including in case of a terrorist release of smallpox
virus (O'Toole, this issue, pp. 540-6).
The current U.S. stockpile contains approximately 15.4 million doses of vaccinia
vaccine (Dryvax) made from the New York City Board of Health strain of vaccinia and was
produced by Wyeth Laboratories in 13 separate lots. The vaccine is lyophylized in glass
vials with rubber stoppers and sealed with a metal band. When rehydrated, each vial
contains 100 doses and has a potency of at least 108 plaque-forming units
(pfu)/ml. Some vials of the vaccine stockpile have shown elevated moisture levels and thus
failed routine quality control testing; however, the vaccine in these vials remains
potent, and the failed lots have not been discarded.
The diluent used to rehydrate the vaccine contains brilliant green, which makes the
vaccine easier to visualize when administered with bifurcated needles. Over time, the
brilliant green has deteriorated, and most of the available diluent does not pass quality
control. Discussions are under way with Wyeth to begin production of sufficient new
diluent for the entire stockpile.
The vaccine is administered by superficial inoculation (scarification) with a
bifurcated needle. Fewer than 1 million bifurcated needles are held as part of the
stockpile. As with the diluent, Wyeth has been requested to produce additional bifurcated
needles.
Vaccinia virus produces adverse reactions in a small percentage of vaccinated persons.
Adverse reactions are treated with vaccinia immune globulin (VIG) (5,400 vials
in stock). Each vial
contains 5 ml of VIG; the recommended dose for postvaccine complications is 0.6 ml per kg
of body weight. This volume is sufficient to treat adverse reactions in approximately 675
adults. Further, the entire stockpile of VIG has been placed on hold while the cause of a
slight pink discoloration is investigated. Until the cause of the discoloration is
determined or another approved supply of VIG is obtained, no vaccinia vaccine is being
released. While unknown, the rate of adverse reactions in today's population is likely to
be greater than seen during the global eradication campaign because of recent increases in
the number of immunocompromised persons. The Department of Defense has recently contracted
the processing of new lots of VIG (to be administered intravenously rather than by the
intramuscular route like existing VIG stocks); however, maintaining adequate stocks of VIG
will remain a challenge.
In the event of release of smallpox virus, persons at high risk and persons exposed but
not yet showing clinical illness would be vaccinated immediately. Intensive case detection
and vaccination of contacts and other persons at risk would follow. All vaccine, including
lots retained after failed quality control tests, would be made available for emergency
use. Previous studies have found that more than 90% of susceptible persons respond to
vaccinia virus with a titer of 107 pocks/ml (2). In an emergency, consideration
would be given to diluting the existing vaccine as much as 10-fold, so that each vial
could conceivably contain 1,000 doses of vaccine, rather than the current 100 doses. The
present vaccine container is sufficiently large to accommodate the added diluent. The
absence of sufficient quantities of VIG to protect against adverse reactions during a mass
immunization campaign would necessitate careful screening of those receiving the vaccine;
some persons with adverse reactions would likely go untreated.
While the intentional release of smallpox virus would represent a global emergency, the
existing national stockpile could be effectively used to limit the spread of disease and
buy time while the pharmaceutical industry begins emergency vaccine production.
James W. LeDuc and John Becher
Centers for Disease Control and Prevention, Atlanta, Georgia, USA
References
- World Health Organization. Report of the meeting of the ad hoc committee on Orthopox
virus infections. Department of Communicable Disease Surveillance and Response. WHO, 14-15
January 1999.
- Cockburn WC, Cross RM, Downie AW, Dumbell KR, Kaplan C, Mclean D, et al. Laboratory
and vaccination studies with dried smallpox vaccines. Bull World Health Organ
1957;16:63-77.
To the Editor: After heavy rains in July 1997, extensive floods occurred along the
Morava River, Czech Republic. Populations of Aedes mosquitoes increased rapidly in
the flooded areas, prompting surveillance for mosquito-borne virus infections in the
Breclav area, South Moravia. We collected 11,334 female mosquitoes (9,100 Aedes vexans,
917 Ae. cinereus, 11 Ae. cantans, 1,074 Ae. sticticus, and
232 Culex p. pipiens) from July through September 1997 and tested them for
virus in 117 monospecific pools by intracranial inoculation of suckling mice. Seven virus
isolates were obtained and identified by complement-fixation and neutralization tests. Six
isolates (five from Ae. vexans, one from Ae. cinereus) were identified as
the bunyavirus Tahyna, California serogroup, and one (strain 97-103 from 57 C. p.
pipiens collected at Lanzhot, 48o40'N, 16o56'E, on September 17)
was identified as the flavivirus West Nile (1). A crossed comparison of 97-103 and
topotype Eg-101 (2) West Nile virus strains and their antisera (prepared in mice by three
intraperitoneal doses at weekly intervals) by plaque reduction neutralization (PRN) on
XTC-2 cells (3,4) showed their antigenic relationships: reciprocal titers of
homologous/heterologous sera were 512/512 in Eg-101 and 512/64 in 97-103. Strain 97-103
has lower virulence than Eg-101 in that it does not kill adult ICR mice and may represent
a subtype of West Nile virus.
Blood samples were obtained from 619 persons seeking treatment at hospital and
outpatient clinics in the Breclav area from June 23 through September 29, 1997. Sera were
inactivated at 56°C for 30 minutes, diluted 1:8, and assayed by PRN for antibodies
against c. 30 plaque-forming units (PFU) per well of West Nile virus strains Eg-101
and 97-103. All sera causing 90% reduction of PFU at 1:8 dilution were titrated, and the
highest serum dilution showing 50% PFU reduction was regarded as the titer. Antibodies
neutralizing West Nile virus were detected in 13 (2.1%) persons: 2.8% of 179 male and 1.8%
of 440 female. Persons with detectable West Nile virus antibody were questioned about
their health history during the previous 5 years, and their medical records were reviewed;
none recalled having had tickborne encephalitis (Central-European encephalitis [CEE] virus
is the only other flavivirus present in Czechland) or having been vaccinated against CEE
or yellow fever virus. Titers of PRN antibodies to CEEV were all below 16. Two of the
seropositive persons had traveled abroad during the last 5 years: one to Croatia in 1996,
and one to South Australia during 1951 to 1994.
Paired serum samples were obtained from 72 of the 619 persons examined. A significant
increase (>4 times) in antibody titer against West Nile virus between the first
(acute-phase) and second (convalescent-phase) samples was detected four times: in 2 of 41
young persons (<16 years of age) and in 2 of 31 adults (>16 years of age). Among the
four seroconverting persons, only the two children had clinical symptoms compatible with
West Nile fever. A 9-year-old boy had fever (39oC) for 4 days, sore throat,
headache, muscle ache, pronounced fatigue, and nausea lasting approximately 6 days, with
recovery after 13 days. Neutralizing antibodies to West Nile virus, Eg-101 and 97-103,
were 64 and 32 on July 22 and 512 and 256 on August 4, respectively. A 9-year-old girl had
fever (38°C-39°C) for 3 days, sore throat, headache, muscle ache, pronounced fatigue,
nausea, vomiting, maculopapular rash (including flushed face), and slightly enlarged
inguinal lymph nodes. The illness lasted approximately 7 days, with complete recovery
after 17 days. Neutralizing antibodies to West Nile virus, Eg-101 and 97-103, were 64 and
32 on August 6 and 256 and 128 on August 20, respectively. Of the remaining nine
seropositive persons lacking paired serum samples, one had severe headache, muscle ache,
prolonged fatigue, nausea, pain on eye movement, maculopapular rash, and insomnia in
summer of 1997. Two other persons had had "summer fever" (sore throat and
lymphadenitis; headache with pain on eye movement) in 1997. The other persons who
seroconverted did not report any substantial illness. In total, clinical symptoms in five
persons are compatible with West Nile fever.
These are the first reported human cases of West Nile fever in Central Europe
(5); an
extensive outbreak occurred in Romania in 1996, with approximately 500 patients
hospitalized and a 4% to 8% fatality rate (6,7). West Nile virus should be viewed as a
potential agent of local sporadic cases, clusters, or outbreaks, even in temperate Europe.
Environmental factors (including human activities) that enhance vector population
densities (heavy rains followed by floods, irrigation, higher than usual temperatures due
to global warming) might produce an increased incidence of West Nile fever and other new
or reemerging mosquito-borne diseases. Surveillance for West Nile fever should monitor
population density and infection rate of principal vectors, antibodies in vertebrates and
exposed human groups, and routine diagnosis of human infections.
Zdenek Hubálek, Jirí Halouzka, and Zina Juricová
Institute of Vertebrate Biology, Academy of Sciences, Brno, Czech Republic
References
- Hubálek Z, Halouzka J, Juricová Z, ebesta O. First
isolation of mosquito-borne West-Nile virus in the Czech Republic. Acta Virol
1998;42:119-20.
- Melnick JL, Paul JR, Riordan JF, Barnett VHH, Goldblum N, Zabin E. Isolation from
human sera in Egypt of a virus apparently identical to West Nile virus. Proc Soc Exp Biol
Med 1951;77:661-5.
- de Madrid AT, Porterfield JS. The
flaviviruses (group B arboviruses): a cross-neutralization study. J Gen Virol
1974;23:91-6.
- Leake CJ, Varma MGR, Pudney M. Cytopathic
effect and plaque formation by arboviruses in a continuous cell line (XTC-2) from the toad
Xenopus laevis. J Gen Virol 1977;35:335-9.
- Hubálek Z, Halouzka J. Arthropod-borne viruses of verte-brates in Europe. Acta
Scientiarum Naturalium Aca-demiae Scientiarum Bohemicae Brno 1996;30, no. 4-5:1-95.
- Le Guenno B, Bougermouh A, Azzam T, Bouakaz R. West
Nile: a deadly virus? Lancet 1996;348:1315.
- Tsai TF, Popovici F, Cernescu C, Campbell GL, Nedelcu NI. West
Nile encephalitis epidemic in southeastern Romania. Lancet 1998;352:767-71.
To the Editor: Unexpected outbreaks of cholera occurred in many areas of the world
in 1997-98, partly because of weather changes associated with the El Niño phenomenon
(1).
Outbreaks caused by antibiotic-resistant Vibrio cholerae O1 and O139 have been
documented in the Indian subcontinent (2-4), Africa (5), and Ukraine
(6).
In Hong Kong, nonduplicate bacterial strains of V. cholerae O1 and O139 isolated
from patients and environmental sources and received in the Public Health Laboratory
between January 1, 1993, and June 30, 1998, were identified by conventional biochemical
tests (7,8) and API 20E (bioMerieux, France); serotyped by slide agglutination with
polyvalent O1 and mono-specific Inaba and Ogawa antisera (Murex, Dartford, United
Kingdom); and checked with O139 antiserum (Denka Seiken, Tokyo, Japan). Biotyped and
antibiotic susceptibilities were determined by the Kirby-Bauer disk-diffusion assay
(8-10). Antibiotics tested included chloramphenicol and tetracycline (from 1993 to 1996)
and ofloxacin (added in routine testing from 1997). V. cholerae isolates available
for further study were tested with the standard broth microdilution method (11) to measure
minimum inhibitory concentrations (MICs) of susceptibilities to chloramphenicol,
tetracycline, and ofloxacin.
No antibiotic resistance was seen in V. cholerae isolates in testing conducted
from 1969 to 1995. The first V. cholerae isolate with reduced susceptibility to
chloramphenicol but sensitive to tetracycline was encountered in Hong Kong in 1996. This
O1 El Tor Ogawa strain was imported from Nepal. Since then, more O1 strains were isolated
that exhibited reduced antibiotic susceptibilities to chloramphenicol and tetracycline but
not to ofloxacin (12). In May 1998, seven V. cholerae O139 strains were isolated
that displayed patterns of antibiotic susceptibilities strikingly different from those of
O1 isolates; the former were all sensitive to tetracycline but showed reduced
susceptibilities to chloramphenicol and ofloxacin. All V. cholerae O1 strains
tested have been susceptible to ofloxacin; O1 isolates falling into intermediate
categories for chloramphenicol and tetracycline susceptibilities (31% and 27.6%,
respectively) were common.
The first isolate of V. cholerae O139 in Hong Kong came from the imported case
of a patient who had traveled to other provinces of China (13,14). Isolation of O139
continued sporadically since then, with six cases between 1993 and the 1st quarter of
1998. In May 1998, a cluster of seven imported cases of V. cholerae O139 were
reported with strains isolated from seven persons who became ill with severe diarrhea
after visiting Zhuhai in Guangdong Province, China. Of 13 V. cholerae O139 isolates
tested, 7 showed intermediate resistance to chloramphenicol and high-level resistance to
ofloxacin (MIC 16 µg/ml) but no resistance to tetracycline (MIC 50s and MIC 90s were 0.25
µg/ml). This is the first evidence of a quinolone-resistant strain of V. cholerae
O139 in Hong Kong. Of the O1 isolates, none were resistant to chloramphenicol and
ofloxacin, but six were resistant to tetracycline (MIC 50s and MIC 90s were 0.25
µg/ml and
8 µg/ml, respectively).
Although all O1 isolates were sensitive to chloramphenicol, there was only a twofold
difference in MIC90 to chloramphenicol between O1 and O139 isolates. MIC90s of ofloxacin
for O139 were nearly 10 times higher than those for O1 strains.
The novel appearance of O139 resistant to ofloxacin with MICs of 16
µg/ml from
Guangdong Province, China, was of special concern. Preliminary results using pulsed-field
gel electrophoresis analysis of chromosomal DNA showed that these ofloxacin-resistant O139
strains had identical fingerprint patterns and probably belonged to the clone that had
caused severe diarrheal disease in the region. Two previous surveys of V. cholerae
antibiotic susceptibilities had not described any ofloxacin-resistant O139 strains
(15,16). The potential for rapid spread of these strains threatens cholera prevention and
control efforts that may still rely on chemotherapy.
Different antimicrobial resistance patterns of V. cholerae O1 and O139 were
noted. Among the resistant O1 isolates, four were local, one was from other provinces of
China, and one was from Thailand. All the resistant O139 isolates were imported from
Guangdong Province, China. Antibiotic resistance was found in strains from local isolates
and from neighboring countries. The unique patterns of antimicrobial resistance for the O1
and O139 isolates suggest different mechanisms of resistance. As quinolones are used
heavily in this region to treat cholera and other enteric diseases, selective pressure
could encourage emergence of ofloxacin resistance. Prudent use of antibiotics should be
exercised during antimicrobial therapy and prophylaxis for cholera and other enteric
diseases to decrease the selection of more resistant clones in our locality.
Kai Man Kam, Kit Yee Luey, Tze Leung Cheung, Kwan Yee Ho, Kwok Hang Mak, and Paul
Thian Aun Saw
Department of Health, Hong Kong SAR Government
References
- World Health Organization, Geneva.
Cholera in 1997. Wkly Epidemiol Rec 1998;73:201-8.
- Gharagozloo RA, Naficy K, Mouin M, Nassirzadeh MH, Yalda R. Comparative
trial of tetracycline, chloramphenicol, and trimethoprim/sulphamethoxazole in eradication
of Vibrio cholerae El Tor. BMJ 1970;4:281-2.
- Glass RI, Huq I, Alim AR, Yunus M. Emergence
of multiply antibiotic-resistant Vibrio cholerae in Bangladesh. J Infect Dis
1980;142:939-42.
- Ramamurthy T, Garg S, Sharma R, Bhattacharya SK, Nair GB, Shimada T, et al. Emergence
of novel strain of Vibrio cholerae with epidemic potential in southern and eastern
India. Lancet 1993;341:703-4.
- Finch MJ, Morris JG Jr, Kaviti J, Kagwanja W, Levine MM. Epidemiology
of antimicrobial resistant cholera in Kenya and east Africa. Am J Trop Med Hyg
1988;39:484-90.
- Clark CG, Kravetz AN, Alekseenko VV, Krendelev YuD, Johnson WM.
Microbiological and epidemiological investigation of cholera epidemic in Ukraine during
1994 and 1995. Epidemiol Infect 1998;121:1-13.
- Cowan ST, Steel KJ. Manual for the identification of medical bacteria. 2nd ed.
Cambridge: Cambridge University Press; 1974.
- Bradfold AK, Bopp CA, Wells JG. Isolation and identification of Vibrio cholerae
O1 from fecal specimens. In: Wachsmuth IK, Blake AB, Olsvik Ø, editors. Vibrio
cholerae and cholera: molecular to global perspectives. Washington: American Society
for Microbiology; 1994. p. 3-26.
- National Committee for Clinical Laboratory Standards. Performance standards for
antimicrobial disk susceptibility tests approved standard. NCCLS document M2-A6. Villanova
(PA): The Committee; 1997.
- National Committee for Clinical Laboratory Standards. Performance standards for
antimicrobial susceptibility testing; NCCLS document M100-S8, 18(1). Villanova (PA): The
Committee; 8th information supplement, 1998.
- National Committee for Clinical Laboratory Standards. Methods for dilution
antimicrobial susceptibility tests for bacteria that grow aerobically. 4th ed. NCCLS
document M7-A4. Villanova (PA): The Committee; 1997.
- Wong W, Ho YY. Imported cholera cases among tours returning from Thailand. Public
Health & Epidemiology Bulletin, Department of Health, Hong Kong. 1998;7:21-4.
- Kam KM, Leung TH, Ho PYY, Ho KY, Saw TA. Outbreak
of Vibrio cholerae O1 in Hong Kong related to contaminated fish tank water.
Public Health 1995;109:389-95.
- Lee SH, Lai ST, Lai JY, Leung NK. Resurgence
of cholera in Hong Kong. Epidemiol Infect 1996;117:43-9.
- Yamamoto T, Nair GB, Albert MJ, Parodi CC, Takeda Y. Survey
of in vitro susceptibilities of Vibrio cholerae O1 and O139 to antimicrobial
agents. Antimicrob Agents Chemother 1995;39:241-4.
- Sciortino CV, Johnson JA, Hamad A. Vitek
system antimicrobial susceptibility testing of O1, O139, and non-O1 Vibrio cholerae.
J Clin Microbiol 1996;34:897-900.
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