Are we Athens or Florence? COVID-19 in historical context.

We have been here before. In 430 BCE, a plague struck Athens, killing as much as 25% of the population. In 1347 CE, the bubonic plague afflicted western Europe for 4 years, killing as much as 50% of the population. The plague of Athens led to a collapse of their religion, cultural norms and democracy. In contrast, the bubonic plague led eventually to the Renaissance, a growth of art, science and humanism. As we contend with the COVID-19 global pandemic, will we become Athens or Florence?

Characterization of systemic and pneumonic murine models of plague infection using a conditionally virulent strain.

Yersinia pestis causes bubonic and pneumonic plague in humans. The pneumonic infection is the most severe and invariably fatal if untreated. Because of its high virulence, ease of delivery and precedent of use in warfare, Y. pestis is considered as a potential bioterror agent. No licensed plague vaccine is currently available in the US. Laboratory research with virulent strains requires appropriate biocontainment (i.e., Biosafety Level 3 (BSL-3) for procedures that generate aerosol/droplets) and secure facilities that comply with federal select agent regulations. To assist in the identification of promising vaccine candidates during the early phases of development, we characterized mouse models of systemic and pneumonic plague infection using the Y. pestis strain EV76, an attenuated human vaccine strain that can be rendered virulent in mice under in vivo iron supplementation. Mice inoculated intranasally or intravenously with Y. pestis EV76 in the presence of iron developed a systemic and pneumonic plague infection that resulted in disease and lethality. Bacteria replicated and severely compromised the spleen, liver and lungs. Susceptibility was age dependent, with younger mice being more vulnerable to pneumonic infection. We used these models of infection to assess the protective capacity of newly developed Salmonella-based plague vaccines. The protective outcome varied depending on the route and dose of infection. Protection was associated with the induction of specific immunological effectors in systemic/mucosal compartments. The models of infection described could serve as safe and practical tools for identifying promising vaccine candidates that warrant further potency evaluation using fully virulent strains in BSL-3 settings.

Lipid A mimetics are potent adjuvants for an intranasal pneumonic plague vaccine.

An effective intranasal (i.n.) vaccine against pneumonic plague was developed. The formulation employed two synthetic lipid A mimetics as adjuvant combined with Yersinia pestis-derived V- and F1-protective antigens. The two nontoxic lipid A mimetics, classed as amino-alkyl glucosaminide 4-phosphates (AGPs) are potent ligands for the Toll-like receptor (TLR) 4. Using a murine (BALB/c) pneumonic plague model, we showed a single i.n. application of the vaccine provided 63% protection within 21 days against a Y. pestis CO92 100 LD50 challenge. Protection reached 100% by 150 days. Using a homologous i.n. 1 degrees /2 degrees dose regimen, with the boost administered at varying times, 63% protection was achieved within 7 days and 100% protection was achieved by 21 days after the first immunization. Little or no protection was observed in animals that received antigens alone, and no protection was observed when the vaccine was administered to BALB/c TLR4 mutant mice. Vaccine-induced serum IgG titers to F1 and V-antigen were reflected in high titers for IgG1 and IgG2a, the latter reflecting a bias for a cell-mediated (TH1) immune response. This intranasal vaccine showed 90% protection in Sprague-Dawley rats challenged with 1000 LD50. We conclude that lipid A mimetics are highly effective adjuvants for an i.n. plague vaccine.

[Exploration on the fulminating plague in Bianjing in 1232 and the climatic factors].

The plague occurred in Bianjing in 1232 was a serious event in the history of Chinese epidemic. It lasted for over 50 days, with a death toll of over 900,000. It is speculated that this is a mass epidemic of pneumonic plague and the pathogen was carried by the Mongolian Army when attacking Bianjing. At that time, the plague spread in Mongolian Army camp and finally involved the suburbs of Bianjing. After the army withdrawal, when Bianjing residents and soldiers went out of the city to collect foods and were unfortunately infected, and thus this dangerous infectious disease was transmitted into the city from the suburbs. Soon, the plague broke out and became epidemic in Bianjing during the 27-day period of 5 May-1 June, because of the cold snap rushed upon Bianjing on 1 June, the unusual weather was the motive for the mass epidemic of the plague. By then, it was popularly recognized as "exogenous cold damage". At present, facing the global climatologic changes, it is of great practical significance to explore the rich materials of plague and the climatic records accumulated in Chinese medicine.

[The serious plague in Kaifeng in the third year of Chunhua of the Northern Song dynasty and the government's response].

In the May of the third year of Chunhua (992) of the Northern Song dynasty, because of a long persistent drought and scorching hot day, the plague occurred and prevailed in Kaifeng, the capital of Northern Song, with a massive death toll, drawing much attention from the government. The cause of plague was related to high temperature, summer-heat warmth in TCM. In response to this, the government issued three imperial edicts: firstly, promulgating the formularies; secondly, sending some doctors to cure patient, as well as giving money and medicines. At the same time, the Imperial Medical Academy to preside over treatment and assigned an inner eunuch to be responsible for intendance; the third was sending the emissary to clear up the prison. This policies of the third year of Chunhua brought important effects to the system of prevention and rescue of epidemic disease in Song dynasty, exerting significant influences on the prevention and treatment of infectious diseases in the Song dynasty.

The Eyam plague revisited: did the village isolation change transmission from fleas to pulmonary?

Back in the 17th century the Derbyshire village of Eyam fell victim to the Black Death, which is thought to have arrived from London in some old clothes brought by a travelling tailor. The village population was 350 at the commencement of plague, of which only 83 survived. Led by the church leaders, the village community realized that the whole surrounding region was at risk from the epidemic, and therefore decided to seal themselves off from the other surrounding villages. In the first 275 days of the outbreak, transmission was predominantly from infected fleas to susceptible humans. From then onward, mortality sharply increased, which indicates a changing in transmission pattern. We hypothesize that the confinement facilitated the spread of the infection by increasing the contact rate through direct transmission among humans. This would be more consistent with pulmonary plague, a deadlier form of the disease. In order to test the above hypothesis we designed a mathematical model for plague dynamics, incorporating both the indirect (fleas-rats-humans) and direct (human-to-human) transmissions of the infection. Our results show remarkable agreement between data and the model, lending support to our hypotheses. The Eyam plague episode is celebrated as a remarkable act of collective self-sacrifice. However, to the best of our knowledge, there were no evidence before that the confinement actually increased the burden payed by the commoners. In the light of our results, it can be said that the hypothesis that confinement facilitated the spread of the infection by increasing the contact rate through direct transmission is plausible.

Immunogeneity and structural organisation of some pLCR-encoded proteins of Yersinia pestis.

A novel method of cultivation of Yersinia pestis EV-76 and its isogenic strains KM-217 (pPst-;pCad+;pFra-) and KM-218 (pPst-;pCad-;pFra-) and careful extraction of Y. pestis proteins (YPPs) permitted isolation of >35 low Ca2+ response plasmid (pLCR)-encoded products, some of which are potentially new members of the LCR family. Immunisation with each YPP demonstrated that 25-, 54-, 72- and 87-kDa YPPs provided the highest level of protection in mice challenged with Y. pestis virulent strain 231. Their immunological relationship was established with monoclonal antibodies (MAbs) and revealed several common properties, including oligosaccharide binding with specificity for N-acetylglucosamine. Affinity chromatography with MAb to the 25-kDa YPP permitted purification of the relevant antigen and its precursor. Their existence in the form of a complicated protein molecule was shown.

[The experimental validation of the advantages of combined emergency (fluoroquinolones) and specific (EV Nalr) prevention of plague versus their sequential use]. / Eksperimental'noe obosnovanie preimushchestv kombinirovannoi ékstrennoi (ftorkhinolony) i spetsificheskoi (EV Nalr) profilaktiki chumy pered ikh posledovatel'nym primeneniem.

Mice immunization with reference vaccine at the early stage of plague infection provided animals survival and prolonged mean survival period up to 2-5 days. Ciprofloxacin, ofloxacin and pefloxacin prevents development of post vaccine immunity at white mice, immunized by reference vaccine strain EV. Nalidixic acid and norfloxacin effect on post vaccine immunity was lower. Use of immunogenic strain EV Nafr (resistant to nalidixic acid and fluoroquinolones) provided antiplague immunity formation at the background of fluoroquinolones prophylaxis. Ciprofloxacin, ofloxacin and pefloxacin used for plague prophylaxis at white mice infected with Yersinia pestis (about 1000 LD50) inhibited postinfective immunity development. Nalidixic acid and norfloxacin didn't demonstrate such effect. Urgent (fluoroquinolones) and specific (EV Nalr) combined prophylaxis was evaluated as more effective for a 5-day period and provided the development of antiplague immunity.

[The plague in Madagascar: epidemiologic data from 1989 to 1995 and the national control program]. / La peste à Madagascar: données épidémiologiques de 1989 à 1995 et programme national de lutte.

After briefly reviewing the history and epidemiological cycle of the plague in Madagascar, we report a detailed analysis of 5,927 suspected cases of plague observed from 1989 to 1995 (average of 846 cases per year). Of those, 1,337 individuals (average of 191 cases per year) were confirmed (by isolation of Yersinia pestis) or indicated to be probable for plague (by positive smears). Since 1994, we observed an increasing number of confirmed and probable cases (252 cases in 1995). Most of the cases occurred between October and April in the central highlands, inside a geographical triangle limited by Alaotra lake, Itasy lake and the city of Fianarantsoa. Two exceptional epidemics occurred in the harbor of Majunga in 1991 and 1995. The bubonic plague was the most frequent clinical from (91.3%), with primarily an inguinal localization (67.8%). The mean case fatality rate was 19% of the confirmed or probable cases (14.8% for the bubonic form and 57.1% for the pneumonic form). The bubonic plague was significantly more frequent between the ages of 5 and 14 years, as compared to the general population, while the pneumonic plague was more frequent over 15 years of age. Males were more effected by the bubonic form, as the sex ratio (m:f) was 1.3. The national control program for plague is being strengthened to improve 1) the patient's early diagnosis and care system; 2) the measures for the prevention of epidemics; 3) the epidemiological surveillance; and 4) the studies on the biology of the plague vectors, rodents and fleas, and the agent, bacilli, in Madagascar.

[Enhancement of treatment efficacy in experimental plague by the sequential administration of antibiotics]. / Povyshenie éffektivnosti lecheniia éksperimental'noi chumy putem posledovatel'nogo vvedeniia antibiotikov.

It was shown that the use of ampicillin, azlocillin or polymyxin 24 or 96 hours after the plague infection at the background of the every-day use of rifampicin in the doses protecting only 30 per cent of the animals from death provided 80-100-percent survival of the animals. With the every-day use of ampicillin, azlocillin or polymyxin in succession with rifampicin there was observed a 3-fold increases in the survival of the albino mice as compared to those exposed to an analogous dose of rifampicin alone. A decrease in the number of administrations of the above drugs and an increase in the intervals between the administration also resulted in a significant rise of the animal survival in comparison with that after the every-day use of a similar dose of rifampicin.

[Multifactorial analysis of combined use of an antibiotic and peptidoglycan of microbial origin in experimental plague]. / Mnogofaktornyi analiz kombinirovannogo primeneniia antibiotika i peptidoglikana mikrobnogo proiskhozhdeniia pri éksperimental'noi chumnoi infektsii.

The combined effect of doxycycline and microbial peptidoglycan was studied with multifactorial analysis. The drugs were used preventively and therapeutically. The preventive use of doxycycline in the subtherapeutic doses in combination with the immunomodulator resulted in a significant increase in the survival rate rather than the average life-span (ALS) of the experimental animals. The therapeutic use of the drugs was more efficient than the preventive one and resulted in higher survival and ALS. By the results of the experiments polynomial statistic models of the second order were developed and the equal level curves characterizing the survival rate and ALS were plotted. The dose-time regimens of the combined use of doxycycline an peptidoglycan were optimized.

[Multifactor study of combined effects of an antibiotic and polysaccharide in experimental infection]. / Izuchenie v mnogofaktornom éksperimente sochetannogo deistviia antibiotika i polisakharida pri éksperimental'noinfektsii.

Multifactorial analysis was applied to the study of the combined effect of doxycycline and a polysaccharide of microbial origin in experimental plague infection. A marked synergistic action of the antibiotic and polysaccharide used in subtherapeutic doses in treatment of the infection was observed. By the results of the experiments polynomial statistic models of the 2nd order were designed and nomographs or equal level lines were plotted. The models and nomographs described the animal survival rate and lifespan within a wide range of the control parameters. The dose/time regimens for the use of the polysaccharide combination with doxycycline were optimized on the basis of the multifactorial analysis.

[A multifactorial analysis of the combined action of an antibiotic and a low-molecular immunomodulator of microbial origin in experimental plague infection]. / Mnogofaktornyi analiz sochetannogo deistviia antibiotika i nizkomolekuliarnogo immunomoduliatora mikrobnogo proiskhozhdeniia pri éksperimental'noi chumnoi infektsii.

The combined effect of doxycycline and a low molecular weight immunomodulator of microbial origin was studied in experimental plague infection with mathematical design of the experiment. Synergism of the action of the antibiotic and immunomodulator used in subtherapeutic doses was observed. The action was the most pronounced when the drugs were applied therapeutically. On the basis of the multifactorial analysis the regimens for the use of the antibiotic and immunomodulator were optimized.