Preparing for biological threats: Addressing the needs of pregnant women.

Intentional release of infectious agents and biological weapons to cause illness and death has the potential to greatly impact pregnant women and their fetuses. We review what is known about the maternal and fetal effects of seven biological threats: Bacillus anthracis (anthrax); variola virus (smallpox); Clostridium botulinum toxin (botulism); Burkholderia mallei (glanders) and Burkholderia pseudomallei (melioidosis); Yersinia pestis (plague); Francisella tularensis (tularemia); and Rickettsia prowazekii (typhus). Evaluating the potential maternal, fetal, and infant consequences of an intentional release of an infectious agent requires an assessment of several key issues: (1) are pregnant women more susceptible to infection or illness compared to the general population?; (2) are pregnant women at increased risk for severe illness, morbidity, and mortality compared to the general population?; (3) does infection or illness during pregnancy place women, the fetus, or the infant at increased risk for adverse outcomes and how does this affect clinical management?; and (4) are the medical countermeasures recommended for the general population safe and effective during pregnancy? These issues help frame national guidance for the care of pregnant women during an intentional release of a biological threat. Birth Defects Research 109:391-398, 2017.© 2017 Wiley Periodicals, Inc.

Improved estimation of the initial number of susceptible individuals in the general stochastic epidemic model using penalized likelihood.

The initial size of a completely susceptible population in a group of individuals plays a key role in drawing inferences for epidemic models. However, this can be difficult to obtain in practice because, in any population, there might be individuals who may not transmit the disease during the epidemic. This short note describes how to improve the maximum likelihood estimators of the infection rate and the initial number of susceptible individuals and provides their approximate Hessian matrix for the general stochastic epidemic model by using the concept of the penalized likelihood function. The simulations of major epidemics show significant improvements in performance in averages and coverage ratios for the suggested estimator of the initial number in comparison to existing methods. We applied the proposed method to the Abakaliki smallpox data.

Bioterrorism: pathogens as weapons.

Biowarfare has been used for centuries. The use of biological weapons in terrorism remains a threat. Biological weapons include infectious agents (pathogens) and toxins. The most devastating bioterrorism scenario would be the airborne dispersal of pathogens over a concentrated population area. Characteristics that make a specific pathogen a high-risk for bioterrorism include a low infective dose, ability to be aerosolized, high contagiousness, and survival in a variety of environmental conditions. The most dangerous potential bioterrorism agents include the microorganisms that produce anthrax, plague, tularemia, and smallpox. Other diseases of interest to bioterrorism include brucellosis, glanders, melioidosis, Q fever, and viral encephalitis. Food safety and water safety threats are another area of concern.

Pulmonary manifestations of other agents: brucella, Q fever, tularemia and smallpox.

Brucella, Q fever, tularemia, and smallpox are all rare infections in the United States but are potential agents of biologic terrorism. The pulmonary manifestations of these infections range from uncommon (brucella and smallpox) to expected (Q fever and tularemia). and all have clinical and radiologic presentations that can be confused with other, more endemic,diseases. Once the release of these agents has been determined, the diagnosis of presenting patients will be straightforward. The onus is on the clinician,however, to be able to recognize the first few, unexpected cases, because early identification will be paramount in helping curb the effect of the outbreak.

Variola virus immune evasion proteins.

Variola virus, the causative agent of smallpox, encodes approximately 200 proteins. Over 80 of these proteins are located in the terminal regions of the genome, where proteins associated with host immune evasion are encoded. To date, only two variola proteins have been characterized. Both are located in the terminal regions and demonstrate immunoregulatory functions. One protein, the smallpox inhibitor of complement enzymes (SPICE), is homologous to a vaccinia virus virulence factor, the vaccinia virus complement-control protein (VCP), which has been found experimentally to be expressed early in the course of vaccinia infection. Both SPICE and VCP are similar in structure and function to the family of mammalian complement regulatory proteins, which function to prevent inadvertent injury to adjacent cells and tissues during complement activation. The second variola protein is the variola virus high-affinity secreted chemokine-binding protein type II (CKBP-II, CBP-II, vCCI), which binds CC-chemokine receptors. The vaccinia homologue of CKBP-II is secreted both early and late in infection. CKBP-II proteins are highly conserved among orthopoxviruses, sharing approximately 85% homology, but are absent in eukaryotes. This characteristic sets it apart from other known virulence factors in orthopoxviruses, which share sequence homology with known mammalian immune regulatory gene products. Future studies of additional variola proteins may help illuminate factors associated with its virulence, pathogenesis and strict human tropism. In addition, these studies may also assist in the development of targeted therapies for the treatment of both smallpox and human immune-related diseases.

Analysis of the complete genome of smallpox variola major virus strain Bangladesh-1975.

We analyzed the 186,102 base pairs (bp) that constitute the entire DNA genome of a highly virulent variola virus isolated from Bangladesh in 1975. The linear, double-stranded molecule has relatively small (725 bp) inverted terminal repeat (ITR) sequences containing three 69-bp direct repeat elements, a 54-bp partial repeat element, and a 105-base telomeric end-loop that can be maximally base-paired to contain 17 mismatches. Proximal to the right-end ITR sequences are another seven 69-bp elements and a 53- and a 27-bp partial element. Sequence analysis showed 187 closely spaced open reading frames specifying putative major proteins containing > or = 65 amino acids. Most of the virus proteins correspond to proteins in current databases, including 150 proteins that have > 90% identity to major gene products encoded by vaccinia virus, the smallpox vaccine. Variola virus has a group of proteins that are truncated compared with vaccinia virus counterparts and a smaller group of proteins that are elongated. The terminal regions encode several novel proteins and variants of other poxvirus proteins that potentially augment variola virus transmissibility and virulence for its only natural host, humans.

The virology of variola minor. Correlation of laboratory tests with the geographic distribution and human virulence of variola isolates.

Several groups of variola isolates were compared in DNA structure, and by four independent biologic markers. Isolates of variola minor from Europe and South America (alastrim virus) could be distinguished from African isolates of variola minor by DNA structure and by two of the four biologic markers. Taken as a group, the properties of African isolates, in general, differed from those of variola major, but this difference was confined to properties which depended (in the laboratory) on the recent history of the virus concerned. The suggestion made previously that there was an "intermediate" or "African" variety of variola virus is discounted. Laboratory tests did not distinguish any individual African isolate from variola major virus. It is concluded that a virus which may be called "alastrim" represents a "fixed" variant of variola virus, whose distribution is consistent with the dramatic spread of variola minor through the Americas and Europe in the early part of this century, and that variola minor in Africa in recent years was due to variola virus which was not alastrim and which laboratory evidence fails to identify as an entity distinguishable from variola major virus.

A successful eradication campaign. Global eradication of smallpox.

Smallpox was the first important disease to be eradicated; it was the success of the Smallpox Eradication Programme that inspired this conference. Several biological reasons favored the eradication of smallpox, the most important of which were probably that recurrent infectivity did not occur, that there was no animal reservoir, and that an effective stable vaccine was available. The importance of smallpox as a disease that travelers might import into countries free of smallpox provided a powerful stimulus for its global eradication. This paper highlights some of the problems associated with the eradication of smallpox in two countries where eradication was difficult, India and Ethiopia, and the measures adopted to overcome the problems. The paper also stresses the importance of the development of methods for the certification of smallpox eradication from countries, from regions, and finally from the whole world. It is noted that close links between field work and research were important throughout the eradication campaign.

Comparison of white pock (h) mutants of monkeypox virus with parental monkeypox and with variola-like viruses isolated from animals.

Monkeypox mutants arising spontaneously or after serial, high multiplicity passage were characterized phenotypically and by restriction endonuclease mapping. Some resemble "whitepox" and variola viruses in several of the markers tested but all are distinguishable phenotypically from these. None resembles "whitepox" viruses in genome structure although near-terminal deletions or symmetrical, terminal rearrangements, relative to parental monkeypox, occurred. "Whitepox" viruses isolated from animals closely resemble variola in both phenotype and genome structure.

Variola virus strains of 1960--1975: the range of intraspecies variability and relationship between properties and geographic origin.

A comparative study of 61 variola virus strains recovered from patients in various geographic regions of the world revealed significant intraspecies variability in some biological properties, established the range of this variability and demonstrated the existence of strains with atypical properties. There was a certain correlation between some laboratory markers of variola virus and the degree of its pathogenicity for man. The prevalence of more virulent and thermoresistant strains in the Hindustan subcontinent and the peculiarity and heterogeneity of the strains circulating in Africa were demonstrated. Alastrim virus was detected among the African isolates.