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PubMed2003

Therapy and short-term prophylaxis of poxvirus infections: historical background and perspectives.

The era of antiviral chemotherapy started more than 50 years with the findings by Domagk and his colleagues that thiosemicarbazones showed activity against vaccinia virus. One of the derivatives, methisazone, was even investigated in the prophylaxis of smallpox. With the successful implementation of the smallpox vaccine, the use of methisazone was not further pursued. Should there be a threat of smallpox or other poxvirus infections, that could not be immediately controlled by vaccination, a therapeutic intervention could be envisaged based on several therapeutic strategies targeted at such cellular enzymes as IMP dehydrogenase, SAH hydrolase, OMP decarboxylase and CTP synthetase, as well as viral enzymes such as the DNA polymerase. Most advanced as a therapeutic or early prophylactic modality to tackle poxvirus infection is cidofovir, which was found active (i) in vitro against all poxviruses studied so far; (ii) in vivo, against vaccinia and cowpox virus infections in experimental animal models; as well as (iii) some human poxvirus infections, such as molluscum contagiosum. In case of an inadvertent poxvirus epidemic, antiviral therapy (i.e. with cidofovir) will offer the possibility to provide short-term prophylaxis, or therapy. Cidofovir should also allow to treat severe complications of vaccination as may happen in for example immunosuppressed patients.

Animals↗

PubMed2004

Mass smallpox immunization program in a deployed military setting.

A prospective, observational study of immunizing over 6,000 active-duty troops against smallpox in a 4-week time period was conducted. It focused on the complications of the vaccine and lost workdays. Comparison is made to the complication rates of earlier smallpox immunization programs. In direct response to elevated bioterrorism concerns, the United States military and civilian first-responders have begun a mass smallpox immunization program. This article reviews the experience with implementing such a program in a forward-deployed location while maintaining military readiness. The objectives were to assess the impact of a mass smallpox immunization program on operations in a forward-deployed military setting and to comment on lessons learned in the screening and immunization process. From January 16, 2003 through February 11, 2003 6,002 members of the United States military were immunized in a forward-deployed location. Information was obtained using data from the Air Force Complete Information Tracking Application (AFCITA) and the Global Expeditionary Medical System (GEMS) we plan to calculate the following Main Outcome Measures data: (1)Percentage of individuals eligible to receive the vaccine, (2) Vaccine take rate by CDC criteria, (3) Number of serious complications, (4) Number of life-threatening complications, and (5) Number of manpower days lost as a complication of the vaccine. A total of 6,739 individuals were screened for vaccination with 6,348 (94%) remaining eligible for the vaccine. The "take" rate for the vaccine was 98.6% as per Centers for Disease Control and Prevention (CDC) criteria. The immunization program produced an additional 156 medical visits (2.6% of patients required one visit). A total of 0.55% of immunized individuals lost one or more work days. In conclusion, a mass smallpox vaccination program can be effectively administered in a forward-deployed military setting despite high tempo military operations with minimal operational impact.

Humans↗

PubMed2000

Measles outbreak in young adults in Victoria, 1999.

OBJECTIVES: To describe an outbreak of measles in Victoria. DESIGN: Case series with cases identified through enhanced passive surveillance and outbreak-related active surveillance. SETTING: State of Victoria, 1999. MAIN OUTCOME MEASURES: Number of cases; epidemiological links and patterns of transmission; patient demographic features and vaccination status; complications. RESULTS: 75 cases were identified (74 laboratory-confirmed; and one epidemiologically linked to a laboratory-confirmed case), with onset between 11 February and 2 May 1999. The first case was in a 21-year-old woman who had recently holidayed in Bali and worked at a large cinema complex in Melbourne. Sixteen cases occurred in people who had contact with the index case at the cinema on one evening. The outbreak spread to regional Victoria and South Australia. Median age of patients was 22 years; 64 (85%) were born between 1968 and 1981, with only one patient in the age group targeted by the primary school component of the 1998 Australian Measles Control Campaign; this child had not been vaccinated. More than a third of patients (28) were hospitalised (total, 97 inpatient days), and five were healthcare workers. CONCLUSIONS: This outbreak was caused by international importation of measles virus. It highlights the change in epidemiology of measles in Australia, from a disease of childhood to one predominantly affecting young adults. A strong two-dose childhood vaccination program, vigilant surveillance, and rapid response to outbreaks will continue to be the basis of measles control, but better protection for young adults should be considered.

Adolescent↗

PubMed2004

Genetic diversity and high proportion of intersubtype recombinants among HIV type 1-infected pregnant women in Kisumu, western Kenya.

The high genetic diversity of HIV-1 continues to complicate effective vaccine development. To better understand the extent of genetic diversity, intersubtype recombinants and their relative contribution to the HIV epidemic in Kenya, we undertook a detailed molecular epidemiological investigation on HIV-1-infected women attending an antenatal clinic in Kisumu, Kenya. Analysis of gag-p24 region from 460 specimens indicated that 310 (67.4%) were A, 94 (20.4%) were D, 28 (6.1%) were C, 9 (2.0%) were A2, 8 (1.7%) were G, and 11 (2.4%) were unclassifiable. Analysis of the env -gp41 region revealed that 326 (70.9%) were A, 85 (18.5%) D, 26 (5.7%) C, 9 (2.0%) each of A2 and G, 4(0.9%) unclassifiable, and 1 (0.2%) CRF02_AG. Parallel analyses of the gag-p24 and env-gp41 regions indicated that 344 (74.8%) were concordant subtypes, while the remaining 116 (25.2%) were discordant subtypes. The most common discordant subtypes were D/A (40, 8.7%), A/D (27, 5.9%), C/A (11, 2.4%), and A/C (8, 1.7%). Further analysis of a 2.1-kb fragment spanning the gag-pol region from 38 selected specimens revealed that 19 were intersubtype recombinants and majority of them were unique recombinant forms. Distribution of concordant and discordant subtypes remained fairly stable over the 4-year period (1996-2000) studied. Comparison of amino acid sequences of gag-p24 and env-gp41 regions with the subtype A consensus sequence or Kenyan candidate vaccine antigen (HIVA) revealed minor variations in the immunodominant epitopes. These data provide further evidence of high genetic diversity, with subtype A as the predominant subtype and a high proportion of intersubtype recombinants in Kenya.

AIDS Serodiagnosis↗

PubMed2006

Complications associated with the bacille Calmette-Guérin vaccination in Ireland.

INTRODUCTION: BCG vaccination is currently recommended for all newborns in Ireland except where specifically contraindicated. This paper describes a marked increase in the number of referrals of patients with localised complications after vaccination to two Dublin paediatric hospitals. This increase coincided with the introduction of a new strain of BCG vaccine METHODS: A population surveillance study was undertaken to determine the frequency and spectrum of complications associated with the new strain of BCG vaccine introduced in Ireland. Patients were identified though review of the infectious disease service case records and microbiology laboratory culture reports for the two year period from August 2002 to July 2004. Prospectively gathered data were supplemented by retrospective chart review. All infants who had inoculation site abscesses, suppurative adenopathy, or non-suppurative adenopathy with nodes > or =2 cm were included. RESULTS: Fifty eight patients presented a median of 13 weeks post-inoculation: 32 with suppurative adenitis, 17 with inoculation site abscess, three with both inoculation site abscess and suppurative adenitis, and six with non-suppurative adenopathy. The overall complication rate was estimated at 1/931 vaccinees with 1/1543 developing suppurative adenitis. Twenty six infants required surgery. DISCUSSION: This series illustrates the role of hospitals in sentinel surveillance and highlights the importance of having a well functioning and responsive system of adverse event reporting. These events raise a serious question as to the suitability of this vaccine strain for use in a national immunisation programme in a country where the prevalence of tuberculous disease is 10.4/100,000.

Abscess↗

PubMed2003

Esterification of cidofovir with alkoxyalkanols increases oral bioavailability and diminishes drug accumulation in kidney.

Smallpox was eradicated by vaccination in the 1970s. However, concerns have arisen about the potential use of variola virus as a biological weapon. Most of the world's population has little residual immunity because systematic vaccination against smallpox ceased in the early 1970s. Vaccination of key elements of the population against smallpox is again being considered. However, there are now large numbers of persons who cannot be safely vaccinated with the current vaccine because of AIDS, immunosuppressive drugs, and certain common skin disorders. It would be useful to have a potent orally active drug as an alternative for these persons in case of an outbreak of smallpox. Alkoxyalkyl esters of cidofovir (CDV) have been shown to be highly active and selective against poxviruses in vitro with activities several logs greater than the activity of unmodified CDV. This is due in large part to increased cellular penetration and conversion to CDV-diphosphate, the active antiviral. In this paper, the oral pharmacokinetics of 14C-labeled hexadecyloxypropyl-cidofir (HDP-CDV), octadecyloxyethyl-cidofir (ODP-CDV), and oleyloxypropyl-cidofir (OLP-CDV) are examined and oral bioavailability and tissue distribution assessed and compared with parenteral CDV. The alkoxyalkyl CDVs are highly orally bioavailable and do not concentrate in kidney, the site of the dose-limiting toxicity of CDV. Plasma and tissue drug levels are many times greater than the in vitro EC(50s) for variola, cowpox, and vaccinia viruses. Thus, the compounds are good candidates for further development for prevention and treatment of smallpox infection and the complications of vaccination.

Administration, Oral↗

PubMed1965