Emerging Infectious Diseases Volume 7 Issue 6

164 Pages·2001·2.5 MB·English

by  CDC

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Perspectives
Could Malaria Reappear in Italy? ..........................................915 R. Romi et al.
Developing New Smallpox Vaccines........................................920 S.R. Rosenthal et al.
Synopsis
Trichomonas vaginalis, HIV, and African-Americans............927 F. Sorvillo et al.
Research
Bioterrorism-Related Inhalational Anthrax:
Cover of Le Vie d’Italia magazine
The First 10 Cases Reported in the United States.................933 J. Jernigan et al.
from 1924, provided courtesy of Dr.
Guido Sabatinelli.
Advanced Age a Risk Factor for Illness Temporally
See page 1061
Associated with Yellow Fever Vaccination..............................945 M. Martin et al.
Rapid Identification of Bordetella pertussis
Dispatches
Pertactin Gene Variants Using LightCycler Real-Time
Polymerase Chain Reaction Combined with Melting
Curve Analysis and Gel Electrophoresis................................952 J. Mäkinen et al.
Vancomycin-Intermediate
Staphylococcus aureus............1023
Modeling Potential Responses to
J.C. Hageman et al.
Smallpox as a Bioterrorist Weapon.........................................959 M.I. Meltzer et al.
Legionella-Like and Other
Hepatitis E Virus Sequences in Swine Related to
Amoebal Pathogens.................1026
Sequences in Humans, the Netherlands..........................................970 W.H.M. van der Poel et al.
T.J. Marrie et al.
A Multistate Outbreak of Escherichia coli
Absence of Vancomycin
O157:H7 Infections Linked to Alfalfa Sprouts
Resistance................................1030
Grown from Contaminated Seeds...........................................977 T. Breuer et al.
P.W. Bodnaruk et al.
Effect of Prevention Measures on Incidence of
Community-Acquired
Human Listeriosis, France, 1987-1997...................................983 V. Goulet et al.
Acinetobacter radioresistens
Bacteremia in an HIV-Positive
The Changing Epidemiology of Leptospirosis in Israel.........990 R. Kariv et al.
Patient......................................1032
P. Visca et al.
The Changing Epidemiology of Malaria in Minnesota..........993 S.A. Seys &
J.B. Bender
The opinions expressed by authors contributing
to this journal do not necessarily reflect the Reduced Fluoroquinolone Susceptibility in
opinions of the Centers for Disease Control and Salmonella enterica Serotypes in Travelers
Prevention or the institutions with which the
authors are affiliated. Returning from Southeast Asia...............................................996 A. Hakanen et al.
Dispatches cont’d Research cont’d
A Cultured Strain of The Serologic Response to Cryptosporidium in
"Helicobacter heilmannii".......1036 HIV-Infected Persons: Implications for
K. Jalava et al. Epidemiologic Research.........................................................1004 J.N.S. Eisenberg et al.
Nontuberculous Mycobacterial rpoB Gene Mutations in Rifampin-Resistant
Disease Following Hot Tub Mycobacterium Identified by Polymerase Chain
Exposure..................................1039 Reaction Single-Stranded Conformational
E.J. Mangione et al. Polymorphism.........................................................................1010 M. Bobadilla-del-Valle
et al.
Catheter-Related Bacteremia...1043
J. Carey et al. Detection and Identification of Spotted Fever Group
Rickettsiae and Ehrlichiae in African Ticks..........................1014 P. Parola et al.
Multistate Outbreak of
Salmonella Baildon..................1046 Vector Competence of Selected North American
K. Cummings et al. Culex and Coquillettidia Mosquitoes
for West Nile Virus..................................................................1018 M.R. Sardelis et al.
Shiga toxin producing
Escherichia coli O157
infection...................................1049 Letters
S.J. O’Brien et al.
Rift Valley Fever Outbreak
Usefulness of Seminested Polymerase Chain
in Mauritania in 1998...............1052
Reaction for Screening Blood Donors at Risk
P. Nabeth et al.
for Malaria in Spain...............................................................1068 A. Benito &J.M. Rubio
Malaria in Illegal Chinese
Immigrants in Italy...................1055
Evidence Against Rapid Emergence of Praziquantel
A. Matteelli et al.
Resistance in Schistosoma haematobium, Kenya................1069 G.C. Coles et al.
Three Cases of Bacteraemia
Evidence Against Rapid Emergence of Praziquantel
caused by Vibrio cholerae O1, —
in Schistosomes Reply to Drs. Coles,
in Blantyre, Malawi.................1059
Lians and Doenhoff................................................................1069 C.H. King et al.
M.A. Gordon et al.
Reiter Syndrome Following Protracted Symptoms
Rabies in Marmosets
of Cyclospora Infection...........................................................1070 V.S. Sloan
(Callithrix jacchus)
Ceará, Brazil............................1062
S.R. Favoretto et al. News and Notes
Aedes (Stegomyia) albopictus
(Skuse), in South Cameroon....1066
Biological Warfare..................................................................1071 J. Lederberg
D. Fontenille & J.C. Toto
About the Cover......................................................................1073 R. Romi
Perspectives
Could Malaria Reappear in Italy?
Roberto Romi,* Guido Sabatinelli,*† and Giancarlo Majori*
*Istituto Superiore di Sanità, Rome, Italy; and †World Health Organization,
Regional Office for Eastern Mediterranean Region, Cairo, Egypt
Because of concern about the possible reintroduction of malaria transmis-
sion in Italy, we analyzed the epidemiologic factors involved and determined
the country’s malariogenic potential. Some rural areas in central and south-
ern Italy have high receptivity because of the presence of potential malaria
vectors. Anopheles labranchiae is probably susceptible to infection with
Plasmodium vivax strains, but less likely to be susceptible to infection with
P. falciparum. Its vulnerability is low because of the low presence of game-
tocyte carriers (imported cases) during the season climatically favorable to
transmission. The overall malariogenic potential of Italy appears to be low,
and reintroduction of malaria is unlikely in most of the country. However, our
investigations showed that the malaria situation merits ongoing epidemio-
logic surveillance.
At the end of World War II, malaria was still present in In 1997, a case of introduced malaria occurred in a rural
vast areas of Italy, mainly in the central and southern area of Grosseto Province, the first since the eradication of
regions and major islands and along northeastern coastal malaria from Italy (9). This event, along with the occasional
areas, with offshoots of hypoendemicity in the Pianura presence of Plasmodium carriers who contracted the disease
Padana (1). The three vectors were Anopheles labranchiae in malaria-endemic areas and the increasing number of
Falleroni and An. sacharovi Favre, both belonging to the so- immigrants from malaria-endemic countries entering Italy,
called maculipennis complex, and An. superpictus Grassi (2). raises concern about the possible reappearance of malaria
An.labranchiae was the principal vector in the central and foci in certain areas. We evaluate the malariogenic potential
southern coastal areas, Sicily, and Sardinia. In the two of Italy and assess the risk for malaria transmission in some
islands, the species was found as high as 1,000 meters above areas, decades after the last analysis of the problem (10,11).
sea level. An. sacharovi was present along much of the
coastal area and in Sardinia, but was most important as vec- Material and Methods
tor in the plains of the northeastern Adriatic coast, where The risk of malaria being reintroduced to an area can be
An. labranchiae was absent. An. superpictus was considered calculated by determining its “malariogenic potential,”
a secondary vector in central and southern Italy and Sicily. which is influenced by three factors: receptivity, infectivity,
In some interior areas of the Pianura Padana, where none of and vulnerability. Receptivity takes into account the
the three vectors was present, low levels of endemicity were presence, density, and biologic characteristics of the vectors;
probably maintained by other species belonging to the macu- infectivity is the degree of susceptibility of mosquitoes to dif-
lipennis complex. ferent Plasmodium species; and vulnerability is the number
A malaria eradication campaign launched in 1947 led to of gametocyte carriers present in the area.
interruption of transmission of Plasmodium falciparum
malaria throughout Italy within 1 year (3). Indoor treatment Receptivity
with DDT (2 g of active ingredient per m2) of houses, stables, To evaluate Italy’s receptivity, we analyzed historical
shelters, and all other rural structures continued into the data and the results of entomologic surveys carried out in
mid-1950s and even later in some hyperendemic areas. In Italy as part of epidemiologic investigations over the last 20
Sardinia, where transmission was particularly high, a spe- years. The vectorial capacity of some Italian populations of
cial program was carried out to eradicate the vector (4). The An. labranchiae was also estimated by the MacDonald
last endemic focus of P. vivax was reported in the province of formula (12).
Palermo, Sicily, in 1956 (5), followed by sporadic cases in the
same province in 1962 (6). The World Health Organization Infectivity
declared Italy free from malaria on November 17, 1970. The possibility that the sporogonic cycle of the various
Since then, almost all reported cases have been imported, Plasmodium species may be completed within a vector is
but their number has risen steadily over the last defined as infectivity. Only a few species of the Anopheles
decade(7,8). genus are capable of becoming infected and transmitting
malaria. Furthermore, for genetic reasons, even mosquito
populations of the same species can differ in sensitivity to
Address for correspondence: Roberto Romi, Laboratorio di Parassito-
logia, Istituto Superiore de Sanitá, Viale Regina Elena, 299, 00161 plasmodia (13) or may be completely resistant to infection
Rome, Italy; fax: [phone]; e-mail: [email protected] with plasmodia from the same species but different
Vol. 7, No.6, November-December 2001 915 Emerging Infectious Diseases
Perspectives
geographic areas. Infectivity in a mosquito population is a ondary (An. atroparvus and An. melanoon) and occasional
determining factor in the assessment of malariogenic poten- (An.algeriensis, An. hyrcanus, and An. claviger) malaria vec-
tial in a given area. We analyzed data in published studies to tors. An. sergenti, a north African species, was implicated in
evaluate the infectivity of Italian vectors. the 1960s in the transmission of a few sporadic case of
malaria on the island of Pantelleria (15).
Vulnerability
Vulnerability in a given territory is determined by the Distribution and Density of Potential Vectors
number of gametocyte carriers during the period in which In northern Italy, in particular the northwestern regions
malaria transmission is possible. To determine the degree of (Veneto and Emilia) where An. sacharovi was present, the
Italy’s vulnerability, a sample of malaria cases reported from last specimens of the vector were found in the province of
1989 to 1996 was selected on the basis of spatial and Rovigo (16); in the last 30 years there have been no further
temporal risk factors for the transmission of malaria. records. No An. sacharovi larvae or adults were recorded in a
Malaria cases reported in Italy in 1997 were also analyzed. recent survey along the northwestern coast of Italy (17).
Because of the limited distribution of vectors potentially However, areas with epidemiologically relevant anopheline
capable of transmitting malaria, we considered only cases in densities still exist in Tuscany (only in Grosseto Province),
Tuscany, Campania, Abruzzo, Molise, Basilicata, Apulia, Calabria, Puglia, Sicily, and Sardinia (14), where hydrogeo-
Calabria, Sicily, and Sardinia. In the past, the season of logic or environmental characteristics are conducive to the
malaria transmission in central and southern Italy lasted development of vectors (Table 1). Residual populations of An.
from June to late September for P. vivax and from July to labranchiae and An. superpictus could still be present along
early September for P. falciparum. We therefore selected the coasts of Abruzzo, Molise (east coast), Campania, and
cases reported from June through September. Basilicata (west coast), but no relevant densities have
recently been reported.
Results
Vectorial Capacity (VC)
Receptivity The high density of anopheline populations reported in
After their drastic reduction as a result of the DDT cam- some areas of Italy does not necessarily imply the resump-
paign, the endophylic anopheline species have begun to tion of malaria. Other entomologic factors must be taken into
reproduce again and in many cases have reached preinter- consideration to estimate the risk of transmission. The VC of
vention densities (14). Of the anopheline species that had a mosquito population is the measure used in epidemiology
been vectors of malaria in Italy, only An. labranchiae and to estimate risk in various geographic areas. It expresses the
An. superpictus are still present in epidemiologically number of potentially infective bites that originate daily
relevant densities (14). In other European and Mediterra- from a case of malaria in a given area or, more precisely,
nean countries, other anophelines have been considered sec- from a carrier of gametocytes capable of infecting all the
Table 1. Distribution and density of Anopheles labranchiae and An. superpictus in five regions of central, southern, and insular Italy
Region At-risk areas Vector Larval breeding sitesa Vector density and capacityb
Tuscany Grosseto province: areas of An.labranchiae Rice fields, agricultural and land 100-1,000 per animal shelter;
intensive rice cultivation (S. reclamation canals, wells. Larval 180-200/person /night. VC in
Carlo, Principina and S. densities in rice fields 5-10 rice fields: P. falc. 7-26; P.
Donato, Orbetello) larvae/sample, elsewhere 0.5-1 vivax 8.3-32.5; VC in natural
larvae/sample breeding sites: P. falc. 0.8-2.9;
P. vivax 0.96-3.3
Apulia Coastal plains of the Adriatic An.labranchiae Land reclamation canals, pools 20-30 per animal shelter
side, from Lesina Lake to for agricultural purposes. Larval
Candelaro River densities 0.02-0.05 larvae/sample
Calabria Coastal plains of the Tirrenian An. labranchiae Larval densities: 20-500 An. labranchiae, 2-10
and Ionian sides and the close An. superpictus An. labranchiae 0.5-1 An. superpictus
hinterland larvae/sample per animal shelter. 10-20
An. superpictus 0.06-0.1 An.labr./person/ night. VC of
larvae/sample An. labranchiae
for P. falciparum 0.8-8.9
Sicily Rural coastal and hilly areas of An. labranchiae Rivers, streams, pools, and canals 10-200 An. labranchiae per
the whole region An. superpictus for agricultural purposes. Larval animal shelter
densities of An. labranchiae 0.03
to 0.5 larvae/sample
Sardinia Rural coastal and hilly areas of An. labranchiae Mainly rivers and streams; 5-40 per animal shelter
the whole region ponds, artificial pools, rice fields
and irrigation canals. Larval
densities 1 to 10 larvae/sample
aFigures refer to areas considered as “at risk” for malaria reintroduction during surveys carried out from 1994 to 1996.
bCalculated at a mean temperature of 25°C (July to August), assuming a sporogonic cycle of 11 days for P. falciparum and 10 days for P. vivax.
VC = vectorial capacity.
Emerging Infectious Diseases 916 Vol. 7, No. 6, November-December 2001
Perspectives
receptive mosquitoes that feed on the carrier. VC is influ- Vulnerability
enced by three factors: the anthropophily, longevity, and Of 885 cases reported in 1997, only 88 (9.9% of the total)
density of the vector. The few recent estimates of the VC of were reported from the nine regions at risk (Table 2). A total
Italian anopheline populations have been limited to of 25 cases (2.8%) occurred during the season favorable to
An.labranchiae (14,18). The first attempt was made in 1978 malaria transmission: 15 from P. falciparum, 9 from P.vivax,
in Calabria: VC was reported as 0.82 to 8.9, with an average and 1 from P. malariae. Most of the patients (64%, n=16)
density of 16 bites per person per night (Coluzzi A. and M., lived in Tuscany. Considering that the highest anopheline
unpub. data). In 1994, in a large area of rice cultivation in mosquito densities were reported in this region, these results
Tuscany (Grosseto Province), VC was very low in early July, are cause for concern. On the other hand, the samples were
constituting no real risk for malaria transmission (<0.01 for quite small (16 patients) and other factors need to be consid-
both P. falciparum and P. vivax). At the beginning and ered. First is the number of patients who live in rural areas,
especially the end of August, VC was high (8 to 32.5), since these are the only areas where the vector can come into
especially for P. vivax, which has a shorter sporogonic cycle contact with a gametocyte carrier. The analysis of samples
than P. falciparum (VC 7 to 26). This high VC is undoubt- shows that most of the 25 at-risk patients (72%, n=18) lived
edly influenced by the high number of bites per person per in an urban area. Another factor is the length of exposure of
night (>200) reported in the area (14). In 1998 in the same the malaria patients to mosquito bites during the disease or
province but in areas where only natural anopheline breed- the length of their stay in a malaria-endemic area. In fact,
ing sites are reported, we calculated the following VCs from all the patients received hospital care in urban areas, which
mid-July through the end of August: P. falciparum 0.8 to 2.9 would certainly limit mosquito-human contact. However, the
and P. vivax 0.96 to 3.3 (<10 bites/person/night) (18). factor that most affects a territory’s vulnerability is the num-
ber of gametocyte carriers—the only persons who can infect
Infectivity mosquitoes—and the length of their potential exposure to
As Plasmodium species have long been eradicated in mosquitoes. Of patients who lived in areas at risk and had
Italy, it is essential to determine whether local vectors are contracted malaria during a period theoretically favorable to
still sensitive to infection with Plasmodium from other areas transmission, only eight became gametocyte carriers (six of
where malaria is present. Few tests of infectivity have been them carriers of P. vivax). These carriers represent 0.7% of
carried out with potential Italian vectors. There are numer- all malaria cases reported in Italy in 1997 and 4% of all the
ous difficulties in rearing mosquitoes of the An. maculipen- gametocyte carriers. In these patients, the average time
nis complex, obtaining blood with vital gametocytes, and between appearance of symptoms and malaria diagnosis
setting up an efficient artificial system that anophelines (when therapy began) was 8.2 days, which is the period when
bite. To resolve these technical difficulties, some samples of patients could have been a source of infection for mosquitoes.
An. atroparvus and An. labranchiae were captured in Italy The cases reported from 1989 to 1996 show similar results:
in the 1970s and transported on several occasions to Kenya, of 5,012 cases, 522 (10.4%) occurred in central and southern
where they were induced to bite P. falciparum carriers Italy; only 184 of these occurred during high-risk months
(19,20). In none of the mosquitoes did the plasmodia carry (June–September). Of 30 gametocyte carriers, 27 were of P.
out the entire cycle and reach the salivary glands. These sus- vivax, 2 of P. falciparum, and 1 of P. ovale.
ceptibility tests were, of course, carried out with an
extremely low number of samples and are insufficient to con- Conclusion
firm that Italian anopheline populations are entirely resis- We investigated Italy’s malariogenic potential and the
tant to infection with African strains of P. falciparum. possibility of a recurrence of transmission there. Our results
Nevertheless, data on the resistance of Italian anopheline indicate the following conclusions. First, some rural areas in
populations to tropical African P.falciparum strains agree central and southern Italy have high receptivity because of
with other observations made in England (21) and Portugal the presence of potential malaria vectors with VC. The fig-
(20) on local An. atroparvus populations. ures for VC were obtained by collecting mosquitoes on
Populations of An. atroparvus from the eastern Russian persons exposed to mosquito bites without any protection
Federation were sensitive to P. vivax strains from Southeast (14). These data are purely theoretical, as it would be quite
Asia (22), and populations from Romania were successfully
infected with P. vivax strains from Korea (23). The marked
tendency of Italian populations of An. atroparvus to bite ani-
Table 2. Italy’s vulnerability to malaria during the season favorable to
mals, together with susceptibility assays carried out so far malaria transmission (June to September) from 1989 to 1997
(19), does not indicate that this species is a malaria vector in No. of
Italy. As for An. labranchiae, this particularly anthropo- cases in No. of
at-risk Total gameto-
philic Mediterranean species can certainly transmit P. vivax, regions no. of cyte
as shown by the 1971 epidemic in Corsica (24), the cases Total No. of and game- carriers in
no. of cases in favora- tocyte at-risk
reported in Greece during 1975–76 (25), and the recent
malaria at-risk ble carrie areas and
sporadic case in Grosseto Province (9). The susceptibility of Year cases regionsa season rs season
An.superpictus to P. falciparum of African origin has not 1989- 5012 522 184 646 30
been tested, but this mosquito is probably sensitive, as it 1996
belongs to the subgenus Cellia, to which the principal Afri- 1997 885 88 25 148 8
can malaria vectors also belong.
aNine regions in central, southern, and insular Italy.
Vol. 7, No. 6, November-December 2001 917 Emerging Infectious Diseases
Perspectives
unlikely for a person to remain exposed to mosquito bites for Dr. Romi is a senior research entomologist in the Laboratory of
long without taking preventive steps. For comparison with Parasitology, Istituto Superiore di Sanità. His research interests
the VC calculated in Italy with that of malaria-endemic include epidemiology of malaria and other vector-borne diseases and
areas, the VC of P. falciparum reaches values >10 and in vector control.
some cases >30 in the hyperendemic conditions in many
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Medicine and Malaria; 1948 May 10-18; Washington, DC. pp.
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kins Press; 1953.
some areas of Italy is epidemiologically significant, and
5. Cefalù M, Gullotta A. Su un episodio epidemico occorso in fase
these areas could become receptive.
di eradicazione della malaria in Sicilia. Rivista di Malariologia
Second, An. labranchiae is susceptible to infection with 1959;38:45-70.
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7. Sabatinelli G, Majori G. Malaria surveillance in Italy: 1986-
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1997 analysis and 1998 provisional data. Euro Surveillance
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1999;4:85-7.
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9. Baldari M, Tamburro A, Sabatinelli G, Romi R, Severini C, Cuc-
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stantly increasing (7,8). after eradication. Lancet 1998;351:1246-8.
The overall malariogenic potential of Italy appears to be 10. Coluzzi A. Dati recenti sulla malaria in Italia e problemi con-
nessi al mantenimento dei risultati raggiunti. Rivista di Malar-
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occur but only in limited rural areas, where high densities of Europe. Oxford: Oxford University Press; 1980.
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don: Oxford University Press; 1957.
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the Italian situation is extremely dynamic and changeable.
influencing the susceptibility of Anopheline mosquitoes to plas-
Sociopolitical factors, in particular, could lead to substantial modial infection. Mosquito News 1975;35: 505-8.
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Entomol 1997;34:263-71.
the density and distribution of vector populations.
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Furthermore, the continuous contact of strains of exotic di Pantelleria e sua probaible implicazione nella transmissione
plasmodia with potential mosquito vectors could lead to di alcuni casi di malaria. Parassitologia 1967;9:69.
long-term selection or adaptation of strains capable of 16. Sepulcri P. La malaria nel Veneto. Istituto Interprovinciale per
la Lotta Antimalarica nelle Venezie. Venice: The Institute;
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Eur Mosq Bull 1999;4:8-10.
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24. Sautet J, Quilici R. A propos de quelques cas de paludisme 25. Zahar AR. Vector bionomics in the epidemiology and control of
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Vol. 7, No. 6, November-December 2001 919 Emerging Infectious Diseases
Perspectives
Developing New Smallpox Vaccines
Steven R. Rosenthal, Michael Merchlinsky, Cynthia Kleppinger, and
Karen L. Goldenthal
Food and Drug Administration, Rockville, Maryland, USA
New stockpiles of smallpox vaccine are required as a contingency for protect-
ing civilian and military personnel against deliberate dissemination of smallpox
virus by terrorists or unfriendly governments. The smallpox vaccine in the cur-
rent stockpile consists of a live animal poxvirus (Vaccinia virus [VACV]) that
was grown on the skin of calves. Because of potential issues with controlling
this earlier manufacturing process, which included scraping VACV lesions from
calfskin, new vaccines are being developed and manufactured by using viral
propagation on well-characterized cell substrates. We describe, from a regula-
tory perspective, the various strains of VACV, the adverse events associated
with calf lymph-propagated smallpox vaccine, the issues regarding selection
and use of cell substrates for vaccine production, and the issues involved in
demonstrating evidence of safety and efficacy.
An attack on the United States with a biological or Smallpox Vaccine
chemical weapon is an eventuality that must be actively The only commercially approved smallpox vaccine avail-
addressed (1,2). Civilian and military public health agencies able for limited use in the United States is Wyeth Dryvax.
are preparing to cope with biological terrorism and warfare This vaccine is a lyophilized preparation of live Vaccinia
through efforts to stockpile vaccines and antibiotics needed virus (VACV), made by using strain New York City calf
to protect against diseases caused by potential biological lymph (NYC_CL), derived from a seed virus of the New York
weapons. New vaccines, such as a new smallpox vaccine, are City Board of Health (NYCBH) strain of VACV that under-
being actively developed, and other biologics are needed to went 22 to 28 heifer passages. The vaccine consists of lyo-
counteract the effects of these weapons on the domestic pop- philized calf lymph containing VACV prepared from live
ulation and military forces. calves. The animals were infected by scarification, and the
Smallpox (Variola major) is a particularly dangerous skin containing viral lesions was physically removed by
biological weapon threat because of its clinical and epidemio- scraping. The lyophilized calf lymph type vaccine is reconsti-
logic properties (2,3). This virus can be manufactured in tuted with a diluent containing 50% glycerin, 0.25% phenol,
large quantities, stored for an extended period of time, and and 0.005% brilliant green. Vaccine prepared by this tradi-
delivered as an infectious aerosol. Evidence indicating that tional manufacturing technique of harvesting VACV from
potential enemies of the United States possess smallpox the skin of cows (and sheep) was used in most regions of the
virus has led to concerns about the susceptibility of U.S. world during the smallpox eradication campaign. The facili-
troops and civilians to the virus and the need to develop ties, expertise, and infrastructure required for producing the
defense strategies (4). With the success of the World Health virus in this way are no longer available. Wyeth Laborato-
Organization (WHO) campaign in the 1970s to eradicate nat- ries discontinued distribution of smallpox vaccine to civilians
urally occurring smallpox and the subsequent discontinua- in 1983(8).
tion of vaccination, a large proportion of the population has This live-virus vaccine also caused rare but serious
no immunity. Case-fatality rates could be higher than 25% if adverse reactions and common local reactions. Effective vac-
smallpox were released as a bioterrorist weapon (5). cination, classified as a “take,” was indicated by the observa-
The U.S. stockpile of smallpox vaccine is maintained by tion of a pustular lesion 6 to 10 days after vaccination at the
the Centers for Disease Control and Prevention (CDC). injection site. This lesion represented a localized infection
These decades-old doses may be inadequate to meet the vac- and was associated with the generation of an immune
cination needs projected after a bioweapon incident. The response. The vaccine take rate has been generally accepted
number of doses needed in various scenarios has recently as a correlate of vaccine efficacy. Specifically, there is a
been discussed (6). In 1972, for example, a single case of direct relationship between the intensity and extent of virus
smallpox in Yugoslavia required 18 million doses of vaccine multiplication and the magnitude and duration of antibody
to stop the spread of disease (7). At least 40 million doses of response (9-13). The vaccine take rate of lesion formation for
vaccine are projected to be needed to respond effectively to a the currently stockpiled vaccine is >90%. Intradermal and
terrorist attack in the United States (6). intramuscular administration of VACV vaccine produces
less severe local reactions, thus decreasing the risk of inad-
vertent autoinoculation or transmission; however, this inoc-
Address for correspondence: Steven R. Rosenthal, CBER/Food and ulation route produces substantially lower responses as
Drug Administration, HFM-475, 1401 Rockville Pike, Rockville, MD measured by enzyme-linked immunosorbent assay (ELISA)
20852, USA; fax: [phone]; e-mail: [email protected] and neutralizing antibody testing (9,13).
Emerging Infectious Diseases 920 Vol. 7, No. 6, November-December 2001