Introduction of the smallpox vaccine in Napoleonic France, as recorded in contemporary medals.

The smallpox vaccine developed by Jenner in 1798 was successfully introduced in France in 1800 with the support of Napoleon Bonaparte. The medals and tokens (coin-like medals) issued to encourage early-day vaccination activities are described in the context of the changing political situation in that country. In 1800 a private society of subscribers, led by the Duke of La Rochefoucauld-Liancourt was created, along with a Vaccine Committee charged with evaluating the safety and efficacy of vaccination before deciding if vaccination should be extended to the entire population. The Vaccine Committee published a positive report in 1803, and in 1804, the Ministry of the Interior established the "Society for the extinction of smallpox in France by means of the propagation of the vaccine". The creation of the Society made smallpox vaccination an official activity of the empire, facilitating collaboration between government agencies. The vaccine institution, established by Napoleon in 1804, continued its functions until 1820 when the Royal Academy of Medicine was created and took over those functions. This case exemplifies the collaboration that was needed between science and politics to rapidly bring the recently developed smallpox vaccine to the needed population.

Gene duplication, gene loss, and recombination events with variola virus shaped the complex evolutionary path of historical American horsepox-based smallpox vaccines.

IMPORTANCE: Modern smallpox vaccines, such as those used against mpox, are made from vaccinia viruses, but it is still unknown whether cowpox, horsepox, or vaccinia viruses were used in the early 20th century or earlier. The mystery began to be solved when the genomes of six historical smallpox vaccines used in the United States from 1850 to 1902 were determined. Our work analyzed in detail the genomes of these six historical vaccines, revealing a complex genomic structure. Historical vaccines are highly similar to horsepox in the core of their genomes, but some are closer to the structure of vaccinia virus at the ends of the genome. One of the vaccines is a recombinant virus with parts of variola virus recombined into its genome. Our data add valuable information for understanding the evolutionary path of current smallpox vaccines and the genetic makeup of the potentially extinct group of horsepox viruses.

Monkeypox (Mpox) requires continued surveillance, vaccines, therapeutics and mitigating strategies.

The widespread outbreak of the monkeypox virus (MPXV) recognized in 2022 poses new challenges for public healthcare systems worldwide. With more than 86,000 people infected, there is concern that MPXV may become endemic outside of its original geographical area leading to repeated human spillover infections or continue to be spread person-to-person. Fortunately, classical public health measures (e.g., isolation, contact tracing and quarantine) and vaccination have blunted the spread of the virus, but cases are continuing to be reported in 28 countries in March 2023. We describe here the vaccines and drugs available for the prevention and treatment of MPXV infections. However, although their efficacy against monkeypox (mpox) has been established in animal models, little is known about their efficacy in the current outbreak setting. The continuing opportunity for transmission raises concerns about the potential for evolution of the virus and for expansion beyond the current risk groups. The priorities for action are clear: 1) more data on the efficacy of vaccines and drugs in infected humans must be gathered; 2) global collaborations are necessary to ensure that government authorities work with the private sector in developed and low and middle income countries (LMICs) to provide the availability of treatments and vaccines, especially in historically endemic/enzootic areas; 3) diagnostic and surveillance capacity must be increased to identify areas and populations where the virus is present and may seed resurgence; 4) those at high risk of severe outcomes (e.g., immunocompromised, untreated HIV, pregnant women, and inflammatory skin conditions) must be informed of the risk of infection and be protected from community transmission of MPXV; 5) engagement with the hardest hit communities in a non-stigmatizing way is needed to increase the understanding and acceptance of public health measures; and 6) repositories of monkeypox clinical samples, including blood, fluids, tissues and lesion material must be established for researchers. This MPXV outbreak is a warning that pandemic preparedness plans need additional coordination and resources. We must prepare for continuing transmission, resurgence, and repeated spillovers of MPXV.

Single Dose of Recombinant Chimeric Horsepox Virus (TNX-801) Vaccination Protects Macaques from Lethal Monkeypox Challenge.

The ongoing global Monkeypox outbreak that started in the spring of 2022 has reinforced the importance of protecting the population using live virus vaccines based on the vaccinia virus (VACV). Smallpox also remains a biothreat and although some U.S. military personnel are immunized with VACV, safety concerns limit its use in other vulnerable groups. Consequently, there is a need for an effective and safer, single dose, live replicating vaccine against both viruses. One potential approach is to use the horsepox virus (HPXV) as a vaccine. Contemporary VACV shares a common ancestor with HPXV, which from the time of Edward Jenner and through the 19th century, was extensively used to vaccinate against smallpox. However, it is unknown if early HPXV-based vaccines exhibited different safety and efficacy profiles compared to modern VACV. A deeper understanding of HPXV as a vaccine platform may allow the construction of safer and more effective vaccines against the poxvirus family. In a proof-of-concept study, we vaccinated cynomolgus macaques with TNX-801, a recombinant chimeric horsepox virus (rcHPXV), and showed that the vaccine elicited protective immune responses against a lethal challenge with monkeypox virus (MPXV), strain Zaire. The vaccine was well tolerated and protected animals from the development of lesions and severe disease. These encouraging data support the further development of TNX-801.

Training, management, and quality of nursing care of vascular access in adult patients: The INCATIV project.

BACKGROUND: More than one billion of peripheral venous catheters are inserted into hospitalized patients every year. This study sought to identify the status of nursing care in vascular accesses in different hospitals and to evaluate the impact of a series of informative and formative interventions aimed at their care. METHODS: Quasi-experimental, multicenter study. A total of 54 nursing professionals of 19 hospitals participated. The intervention consisted of informative talk and three training sessions related to the care and maintenance of vascular accesses and intravenous therapy in the hospital-admitted adult population. This was delivered in four years, with eight periodic cross-sectional assessments conducted before and after each intervention. To assess quality of nursing care in vascular accesses and intravenous therapy, a quality indicator called Standard Variable (VES), was developed and validated with the Delphi methodology. RESULTS: A total of 21,108 patients, aged 64.0 years (SD 18.3), were assessed, of which 78.3% (16,516) had some type of vascular access inserted. An average of 22.1% (95% CI: 21.4-22.7) were classified as optimal. In total, 3218 nursing care professionals took part in the training activities. The VES indicator grew steadily throughout the study, raising from 7.8% to 37.6%. Changes were statistically significant between those time points in which one of the described interventions was delivered; however, there were no significant changes between time points with no intervention. CONCLUSIONS: This study supports that continuous training interventions can produce improvements in the quality of nursing care and reduce complications in patients with vascular accesses. In addition, the VES indicator was a useful and simple tool to measure quality, but the experience with its use suggests continuous research in the search for standardized indicators that objectify the evaluation and evolution of care.

Re-assembly of nineteenth-century smallpox vaccine genomes reveals the contemporaneous use of horsepox and horsepox-related viruses in the USA.

According to a recent article published in Genome Biology, Duggan and coworkers sequenced and partially assembled five genomes of smallpox vaccines from the nineteenth century. No information regarding the ends of genomes was presented, and they are important to understand the evolutionary relationship of the different smallpox vaccine genomes during the centuries. We re-assembled the genomes, which include the largest genomes in the vaccinia lineage and one true horsepox strain. Moreover, the assemblies reveal a diverse genetic structure in the genome ends. Our data emphasize the concurrent use of horsepox and horsepox-related viruses as the smallpox vaccine in the nineteenth century.

Ethical conflicts in COVID-19 times.

The COVID-19 pandemic has created new challenges on multiple fronts including a few ethical concerns. Timely and appropriate access to health services and the need to protect vulnerable people are some of them. An important aspect to consider, at the global level, is the frailty of health systems in many developing countries and the constant threat of these collapsing due to shortage of resources and medical supply. Special attention should be placed towards protecting the health of care workers who are highly exposed to SARS-CoV-2 infection. Research and clinical trials involving COVID-19 patients and healthy human volunteers must be done in strict adherence to the fundamental principles of bioethics, even if finding a solution is an urgent need. Shared responsibility must be assumed as we collectively face a common problem and ethical conflicts must be resolved using, as reference, the guidelines developed by the World Health Organization and other relevant international and national organizations. This would allow responsible action in the face of the pandemic without harming human rights, the individual and collective well-being.

Early smallpox vaccine manufacturing in the United States: Introduction of the "animal vaccine" in 1870, establishment of "vaccine farms", and the beginnings of the vaccine industry.

For the first 80-90 years after Jenner's discovery of vaccination in 1796, the main strategy used to disseminate and maintain the smallpox vaccine was arm-to-arm vaccination, also known as Jennerian or humanized vaccination. A major advance occurred after 1860 with the development of what was known as "animal vaccine", which referred to growing vaccine material from serial propagation in calves before use in humans. The use of "animal vaccine" had several advantages over arm-to-arm vaccination: it would not transmit syphilis or other human diseases, it ensured a supply of vaccine even in the absence of the spontaneous occurrence of cases of cowpox or horsepox, and it allowed the production of large amounts of vaccine. The "animal vaccine" concept was introduced in the United States in 1870 by Henry Austin Martin. Very rapidly a number of "vaccine farms" were established in the U.S. and produced large quantities of "animal vaccine". These "vaccine farms" were mostly established by medical doctors who saw an opportunity to respond to an increasing demand of smallpox vaccine from individuals and from health authorities, and to make a profit. The "vaccine farms" evolved from producing only smallpox "animal vaccine" to manufacturing several other biologics, including diphtheria- and other antitoxins. Two major incidents of tetanus contamination happened in 1901, which led to the promulgation of the Biologics Control Act of 1902. The US Secretary of the Treasury issued licenses to produce and sell biologicals, mainly vaccines and antitoxins. Through several mergers and acquisitions, the initial biologics licensees eventually evolved into some of the current major American industrial vaccine companies. An important aspect that was never clarified was the source of the vaccine stocks used to manufacture the smallpox "animal vaccines". Most likely, different smallpox vaccine stocks were repeatedly introduced from Europe, resulting in polyclonal vaccines that are now recognized as "variants" more appropriately than "strains". Further, clonal analysis of modern "animal vaccines" indicate that they are probably derived from complex recombinational events between different strains of vaccinia and horsepox. Modern sequencing technologies are now been used by us to study old smallpox vaccine specimens in an effort to better understand the origin and evolution of the vaccines that were used to eradicate the smallpox.

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.

Early vaccine advocacy: Medals honoring Edward Jenner issued during the 19th century.

The results from the first vaccination experiments published by Edward Jenner in 1798 were widely disseminated and consequently Jennerian vaccination was rapidly introduced in Europe and elsewhere. One of the reasons for the rapid spread of vaccination was that Jenner championed the procedure as a public health tool and not just as a mean to achieve individual protection. Vaccination was promoted by the highest levels of government in Germany where the vaccine was introduced in 1799 and also in France, where the vaccine arrived in 1800. Medals were used to promote vaccination both rewarding parents of vaccinated children as well as meritorious vaccinators. The first medal mentioning the name of Jenner was minted in Germany in 1803 followed by others, minted in Germany, Italy, France and England. Numerous other vaccine medals were made during the 19th century as an early and little known approach to advocating for vaccination.

La Nominación de Humberto Fernández-Morán al Premio Nobel en Fisiología o Medicina de 1968 / The nomination of Humberto Fernandez-Moran to the Nobel Prize in Physiology or Medicine 1968

En 1968 Humberto Fernández-Morán fue nominado por dos personas para el Premio Nobel en Fisiología o Medicina por sus contribuciones al estudio de la ultraestructura celular por medio del uso del microscopio electrónico, con especial mención al desarrollo de la cuchilla de diamante. Sin embargo, en ese año no fue seleccionado para su ulterior consideración para el premio.

Role of Melatonin in Aluminum-Related Neurodegenerative Disorders: a Review.

Aluminum (Al), a potentially neurotoxic element, provokes various adverse effects on human health such as dialysis dementia, osteomalacia, and microcytic anemia. It has been also associated with serious neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, and Parkinsonism dementia of Guam. The "aluminum hypothesis" of AD assumes that the metal complexes can potentiate the rate of aggregation of amyloid-ß (Aß), enhancing the toxicity of this peptide, and being able of contributing to the pathogenesis of AD. It has been supported by a number of analytical, epidemiological, and neurotoxicological studies. On the other hand, melatonin (Mel) is a potent direct free radical scavenger and indirect antioxidant, which acts increasing the activity of important related antioxidant enzymes, and preventing oxidative stress and cell death of neurons exposed to Aß-induced neurotoxicity. Therefore, Mel might be useful in the treatment of AD by reducing the Aß generation and by inhibiting mitochondrial cell death pathways. The present review on the role of Mel in Al-related neurodegenerative disorders concludes that the protective effects of this hormone, together with its low toxicity, support the administration of Mel as a potential supplement in the treatment of neurological disorders, in which oxidative stress is involved.

Intragastric Administration of Lactobacillus plantarum and 2,2'-Dithiodipyridine-Inactivated Simian Immunodeficiency Virus (SIV) Does Not Protect Indian Rhesus Macaques from Intrarectal SIV Challenge or Reduce Virus Replication after Transmission.

A major obstacle to development of an effective AIDS vaccine is that along with the intended beneficial responses, the immunization regimen may activate CD4+ T cells that can facilitate acquisition of human immunodeficiency virus (HIV) by serving as target cells for the virus. Lu et al. (W. Lu et al., Cell Rep 2:1736-1746, 2012, https://doi.org/10.1016/j.celrep.2012.11.016) reported that intragastric administration of chemically inactivated simian immunodeficiency virus SIVmac239 and Lactobacillus plantarum (iSIV-L. plantarum) protected 15/16 Chinese-origin rhesus macaques (RMs) from high-dose intrarectal SIVmac239 challenge at 3 months postimmunization. They attributed the observed protection to induction of immune tolerance, mediated by "MHC-Ib/E-restricted CD8+ regulatory T cells that suppressed SIV-harboring CD4+ T cell activation and ex vivo SIV replication in 15/16 animals without inducing SIV-specific antibodies or cytotoxic T." J.-M. Andrieu et al. (Front Immunol 5:297, 2014, https://doi.org/10.3389/fimmu.2014.00297) subsequently reported protection from infection in 23/24 RMs immunized intragastrically or intravaginally with iSIV and Mycobacterium bovis BCG, L. plantarum, or Lactobacillus rhamnosus, which they ascribed to the same tolerogenic mechanism. Using vaccine materials obtained from our coauthors, we conducted an immunization and challenge experiment with 54 Indian RMs and included control groups receiving iSIV only or L. plantarum only as well as unvaccinated animals. Intrarectal challenge with SIVmac239 resulted in rapid infection in all groups of vaccinated RMs as well as unvaccinated controls. iSIV-L. plantarum-vaccinated animals that became SIV infected showed viral loads similar to those observed in animals receiving iSIV only or L. plantarum only or in unvaccinated controls. The protection from SIV transmission conferred by intragastric iSIV-L. plantarum administration reported previously for Chinese-origin RMs was not observed when the same experiment was conducted in a larger cohort of Indian-origin animals.IMPORTANCE Despite an increased understanding of immune responses against HIV, a safe and effective AIDS vaccine is not yet available. One obstacle is that immunization may activate CD4+ T cells that may act as target cells for acquisition of HIV. An alternative strategy may involve induction of a tolerance-inducing response that limits the availability of activated CD4+ T cells, thus limiting the ability of virus to establish infection. In this regard, exciting results were obtained for Chinese-origin rhesus macaques by using a "tolerogenic" vaccine, consisting of intragastric administration of Lactobacillus plantarum and 2,2'-dithiodipyridine-inactivated SIV, which showed highly significant protection from virus transmission. In the present study, we administered iSIV-L. plantarum to Indian-origin rhesus macaques and failed to observe any protective effect on virus acquisition in this experimental setting. This work is important because it contributes to the overall assessment of the clinical potential of a new candidate AIDS vaccine platform based on iSIV-L. plantarum.

Equination (inoculation of horsepox): An early alternative to vaccination (inoculation of cowpox) and the potential role of horsepox virus in the origin of the smallpox vaccine.

For almost 150 years after Edward Jenner had published the "Inquiry" in 1798, it was generally assumed that the cowpox virus was the vaccine against smallpox. It was not until 1939 when it was shown that vaccinia, the smallpox vaccine virus, was serologically related but different from the cowpox virus. In the absence of a known natural host, vaccinia has been considered to be a laboratory virus that may have originated from mutational or recombinational events involving cowpox virus, variola viruses or some unknown ancestral Orthopoxvirus. A favorite candidate for a vaccinia ancestor has been the horsepox virus. Edward Jenner himself suspected that cowpox derived from horsepox and he also believed that "matter" obtained from either disease could be used as preventative of smallpox. During the 19th century, inoculation with cowpox (vaccination) was used in Europe alongside with inoculation with horsepox (equination) to prevent smallpox. Vaccine-manufacturing practices during the 19th century may have resulted in the use of virus mixtures, leading to different genetic modifications that resulted in present-day vaccinia strains. Horsepox, a disease previously reported only in Europe, has been disappearing on that continent since the beginning of the 20th century and now seems to have become extinct, although the virus perhaps remains circulating in an unknown reservoir. Genomic sequencing of a horsepox virus isolated in Mongolia in 1976 indicated that, while closely related to vaccinia, this horsepox virus contained additional, potentially ancestral sequences absent in vaccinia. Recent genetic analyses of extant vaccinia viruses have revealed that some strains contain ancestral horsepox virus genes or are phylogenetically related to horsepox virus. We have recently reported that a commercially produced smallpox vaccine, manufactured in the United States in 1902, is genetically highly similar to horsepox virus, providing a missing link in this 200-year-old mystery.