A short history of biological warfare

Biological weapons have been used in war from the start of recorded history. This article reviews the history of the subject, including the outbreak of the Black Death and the use of smallpox against American Indians. The new science of microbiology was misused from soon after its start and, despite the 1925 Geneva Protocol, the Japanese experimented extensively on prisoners in China. The Allies carried out extensive research during the Second World War, notably the United Kingdom into anthrax on Gruinard Island and the United States into a variety of agents. Despite the 1972 Biological Weapons Convention (BWC), a major programme continued in the former Soviet Union (leading to an accidental outbreak of anthrax). Most recently Iraq was revealed as having an extensive programme, with weaponization of large amounts of various agents, and several terrorists groups have attempted to use biological agents as weapons. Modern developments in biotechnology could lead to even more serious developments, and effective preventive measures, including strengthening of the BWC, are imperative.     

Disabling complement regulatory activities of vaccinia virus complement control protein reduces vaccinia virus pathogenicity

Poxviruses encode a repertoire of immunomodulatory proteins to thwart the host immune system. One among this array is a homolog of the host complement regulatory proteins that is conserved in various poxviruses including vaccinia (VACV) and variola. The vaccinia virus complement control protein (VCP), which inhibits complement by decaying the classical pathway C3-convertase (decay-accelerating activity), and by supporting inactivation of C3b and C4b by serine protease factor I (cofactor activity), was shown to play a role in viral pathogenesis. However, the role its individual complement regulatory activities impart in pathogenesis, have not yet been elucidated. Here, we have generated monoclonal antibodies (mAbs) that block the VCP functions and utilized them to evaluate the relative contribution of complement regulatory activities of VCP in viral pathogenesis by employing a rabbit intradermal model for VACV infection. Targeting VCP by mAbs that inhibited the decay-accelerating activity as well as cofactor activity of VCP or primarily the cofactor activity of VCP, by injecting them at the site of infection, significantly reduced VACV lesion size. This reduction however was not pronounced when VCP was targeted by a mAb that inhibited only the decay-accelerating activity. Further, the reduction in lesion size by mAbs was reversed when host complement was depleted by injecting cobra venom factor. Thus, our results suggest that targeting VCP by antibodies reduces VACV pathogenicity and that principally the cofactor activity of VCP appears to contribute to the virulence.     

A randomized,double-blind,controlled clinical trial to evaluate the efficacy and safety of CJ-50300, a newly developed cell culture-derived smallpox vaccine,in healthy volunteers

A randomized, double-blind, controlled clinical trial was conducted to evaluate the efficacy and safety of CJ-50300, a newly developed cell culture-derived smallpox vaccine, and to determine its minimum effective dose. The overall rates of cutaneous “take” reaction and humoral and cellular immunogenicity in CJ-50300 vaccinees were 100% (123/123), 99.2% (122/123), and 90.8% (109/120), respectively, and these rates did not differ significantly between the conventional-dose and the low-dose CJ-50300 (1.0 × 10⁸ and 1.0 × 10⁷ plaque-forming units/mL, respectively) (P > 0.05 for each). No serious adverse reaction was observed. However, one case of possible generalized vaccinia occurred in the conventionally dosed group [ClinicalTrials.gov Identifier: NCT00607243].     

Single-shot immunization with recombinant adenovirus encoding vaccinia virus glycoprotein A27L is protective against a virulent respiratory poxvirus infection

Significant safety issues have emerged concerning the general use of DRYVAX^® vaccine. Vaccination with replication-defective recombinant adenovirus (rAd) vaccines may offer a safer and effective alternative to live vaccinia virus (VV) vaccination. Six individual poxvirus glycoproteins: A33R, A34R, A36R, B5R, A27L or L1R that are normally expressed on the surface of infectious vaccinia virus were encoded in rAd vaccines and tested in mice in this study. A single-shot intramuscular injection of rAd encoding A27L protected mice against a lethal intranasal challenge with VV at 4 weeks post-vaccination. By 10 weeks post-vaccination, a significant decrease in post-challenge morbidity was observed that correlated with potent neutralizing antibody responses and the emergence of specific polyfunctional T cell responses. The immunogenicity and protective efficacy of rAd-A27L immunization persisted for at least 35 weeks post-vaccination. This study is the first demonstration that a single-shot subunit vaccine encoding a poxvirus protein confers protection against the mortality and morbidity associated with poxvirus infection.     

Immunogenicity and protection efficacy of subunit-based smallpox vaccines using variola major antigens

The viral strain responsible for smallpox infection is variola major (VARV). As a result of the successful eradication of smallpox with the vaccinia virus (VACV), the general population is no longer required to receive a smallpox vaccine, and will have no protection against smallpox. This lack of immunity is a concern due to the potential for use of smallpox as a biological weapon. Considerable progress has been made in the development of subunit-based smallpox vaccines resulting from the identification of VACV protective antigens. It also offers the possibility of using antigens from VARV to formulate the next generation subunit-based smallpox vaccines. Here, we show that codon-optimized DNA vaccines expressing three VARV antigens (A30, B7 and F8) and their recombinant protein counterparts elicited high-titer, cross-reactive, VACV neutralizing antibody responses in mice. Vaccinated mice were protected from intraperitoneal and intranasal challenges with VACV. These results suggest the feasibility of a subunit smallpox vaccine based on VARV antigen sequences to induce immunity against poxvirus infection.     

Three different paths to introduce the smallpox vaccine in early 19th century United States

The ancient technique of variolation (inoculation of the smallpox) which was introduced in the United States in 1721 was replaced by vaccination (inoculation of the cowpox) soon after the procedure was published by Edward Jenner in 1798. Benjamin Waterhouse is recognized as the introducer of smallpox vaccination in the United States having conducted the first vaccination in Boston on 8 July 1800, although other American physicians also played an important role in extending vaccination in the East Coast of the United States. A different route of introduction brought the smallpox vaccine from Mexico to New Mexico (March 1805) and Texas (April 1806) which at that time where part of the Viceroyalty of New Spain. The vaccine was brought to California in 1817 by Russian merchants who obtained it in Peru, where the vaccine had arrived in 1806 with the Spanish Philanthropic Expedition of the Vaccine. It took almost 150 years of vaccination efforts before the last natural outbreak of smallpox occurred in the United States in 1949.     

The beginnings of smallpox vaccination in Spain seen through the correspondence of Ignacio María Ruiz de Luzuriaga (1801–1802)

Edward Jenner’s discovery of the smallpox vaccine spread rapidly across Europe. In Spain, vaccinations first took place in December 1800 and the practice flourished upon the private initiative of doctors, surgeons, state officials and members of the nobility in different parts of the country. Ignacio María Ruiz de Luzuriaga, secretary of the Royal Academy of Medicine of Madrid, is considered in medical historiography as a key figure of the introduction of the smallpox vaccine in Spain. Ruiz de Luzuriaga had a major role as a disseminator of the Jennerian technique and as a distributor of the vaccine fluid. Given his prestige as a doctor and his position in the Royal Academy, he was commissioned to establish a scientific and academic corpus on preventive measures to foster their understanding, uptake and good practice among Spanish vaccinators. He also attempted to create a Central Vaccine Committee, such as that existing in other European countries. The Royal Academy kept records of his activity which have been filed and catalogued in a documentary set entitled ‘Papeles sobre la vacuna’ [Vaccine Papers]. This archive has not been studied in depth to date. These documents allow identifying a network of correspondents set up by Ruiz de Luzuriaga. He provided these correspondents with the vaccine and asked them to report back on the vaccination progress made in their municipalities. This correspondence provides an account of how the first immunisations in Spain unravelled, as well as of the initial concerns that accompanied the introduction of the vaccine.     

“胎毒外感说”与中国古代防治天花的成就

“胎毒外感说”对中国古代防治天花的实践起了决定性的指导作用，使中国不仅在琴纳之前近６００年就在理论和实践两方面认识到人类以外的其他温血胎生动物也有可能患上天花这一事实，而且达到了近代天花病毒被发现之前关于天花致病因的最科学的认识