Convalescent Blood: Current Perspective on the Efficacy of a Legacy Approach in COVID-19 Treatment.

Since early 2020, COVID-19 has wreaked havoc in many societies around the world. As of the present, the SARS-CoV-2-borne disease is propagating in almost all countries, affecting hundreds of thousands of people in an unprecedented way. As the name suggests, the novel coronavirus, widely known as SARS-CoV-2, is a new emerging human pathogen. A novel disease of relatively unknown origin, COVID-19 does not seem to be amenable to the currently available medicines since there is no specific cure for the disease. In the absence of any vaccine or effective antiviral medication, we have no tools at our disposal, but the method of quarantine, be it domestic or institutional, to hinder any further progression of this outbreak. However, there is a record of physicians in the past who practiced convalescent blood transfusion. To their awe, the method seemed to be useful. It is anticipated that these contemporary methods will outdo any other vaccination process in the time being, as blood transfusion is instead a cost-effective and time-friendly technique. Following a successful trial, this new approach of contemporary nature to a viral disease may serve as an emergency intervention to intercept infectious outbreaks and prevent an impending epidemic/pandemic. In this review, we document the most recent evidence regarding the efficiency of convalescent plasma and serum therapy on SARS, MERS, and particularly COVID-19, while discussing potential advantages and possible risks of such practice.

History, extensive characterization and challenge of anti-tetanus serum from World War I: exciting remnants and deceived hopes : Centenarian IgGs lost their neutralization capacity.

During World War I (WWI), infectious diseases including tetanus were among the most important causes of death. Even though its efficacy was somewhat controversial before the war, tetanus antiserum played a key role in reducing the mortality of this disease. A vial of tetanus antiserum dating back from WWI, left behind on the French battlefield by the US Army, was borrowed from a private collection and opened. The serum contained within was characterized by orthogonal biochemical techniques to determine if any neutralizing IgGs could remain after 100 years of storage. In vitro analysis by Size Exclusion Chromatography and Serum Protein Electrophoresis suggested the presence of residual IgG. In spite of our hopes, these IgGs were not able to protect mice against tetanus toxin challenge in a neutralizing assay. Even though our results indicate the presence of remaining IgGs inside the serum, they were functionally disabled. These results show that obscurity alone is insufficient to protect IgGs from degradation over very long periods of time at room temperature. HIGHLIGHTS: Tetanus antiserum found its place in the therapeutic arsenal during World War I A century-old vial of tetanus antiserum was opened for biochemical and in vivo characterization Biochemical assays revealed the presence of proteins having all the characteristics of IgGs The serum was unable to protect mice against toxinic challenge.

Limited Innovations After More Than 65 Years of Immunoglobulin Replacement Therapy: Potential of IgA- and IgM-Enriched Formulations to Prevent Bacterial Respiratory Tract Infections.

Patients with primary immunoglobulin deficiency have lower immunoglobulin levels or decreased immunoglobulin function, which makes these patients more susceptible to bacterial infection. Most prevalent are the selective IgA deficiencies (~1:3,000), followed by common variable immune deficiency (~1:25,000). Agammaglobulinemia is less common (~1:400,000) and is characterized by very low or no immunoglobulin production resulting in a more severe disease phenotype. Therapy for patients with agammaglobulinemia mainly relies on prophylactic antibiotics and the use of IgG replacement therapy, which successfully reduces the frequency of invasive bacterial infections. Currently used immunoglobulin preparations contain only IgG. As a result, concurrent IgA and IgM deficiency persist in a large proportion of agammaglobulinemia patients. Especially patients with IgM deficiency remain at risk for recurrent infections at mucosal surfaces, which includes the respiratory tract. IgA and IgM have multiple functions in the protection against bacterial infections at the mucosal surface. Because of their multimeric structure, both IgA and IgM are able to agglutinate bacteria efficiently. Agglutination allows for entrapment of bacteria in mucus that increases clearance from the respiratory tract. IgA is also important for blocking bacterial adhesion by interfering with bacterial adhesion receptors. IgM in its place is very well capable of activating complement, therefore, it is thought to be important in complement-mediated protection at the mucosal surface. The purpose of this Mini Review is to highlight the latest advances regarding IgA- and IgM-enriched immunoglobulin replacement therapy. We describe the different IgA- and IgM-enriched IgG formulations, their possible modes of action and potential to protect against respiratory tract infections in patients with primary immunoglobulin deficiencies.

Contribution of physiologists to the identification of the humoral component of immunity in the 19th century.

The history of antimicrobial humoral immunity usually focuses on the works of the German school at the end of the 19th century, born in the tradition of chemistry and disinfection. Starting from an old quarrel of priority about serotherapy between Emil von Behring (1854-1917) and the French physiologists Charles Richet (1850-1935) and Jules Héricourt (1850-1938), we first confirm that the latter stated the principle of serotherapy in 1888 and put it into practice before the seminal Behring's article in 1890, observing several adverse effects of this new immunotherapy. We also find that researchers who can be considered heirs of the French school of Physiology founded by Claude Bernard (1813-1878) also investigated the field of humoral immunity in the 1870-1880s. Maurice Raynaud (1834-1881), Auguste Chauveau (1827-1917), and eventually Charles Richet applied the experimental method of Claude Bernard to the young field of microbiology, illustrating a movement called by Jacques Léonard "physiologization of the pasteurism." However, the contribution of physiologists in this field started before Louis Pasteur, leading to the conclusion that physiologists and chemists synergistically contributed to the birth of bacteriology and immunology.

Benefits of using heterologous polyclonal antibodies and potential applications to new and undertreated infectious pathogens.

BACKGROUND: Passive immunotherapy using polyclonal antibodies (immunoglobulins) has been used for over a century in the treatment and post-exposure prophylaxis of various infections and toxins. Heterologous polyclonal antibodies are obtained from animals hyperimmunised with a pathogen or toxin. AIMS: The aims of this review are to examine the history of animal polyclonal antibody therapy use, their development into safe and effective products and the potential application to humans for emerging and neglected infectious diseases. METHODS: A literature search of OVID Medline and OVID Embase databases was undertaken to identify articles on the safety, efficacy and ongoing development of polyclonal antibodies. The search contained database-specific MeSH and EMTREE terms in combination with pertinent text-words: polyclonal antibodies and rare/neglected diseases, antivenins, immunoglobulins, serum sickness, anaphylaxis, drug safety, post marketing surveillance, rabies, human influenza, Dengue, West Nile, Nipah, Hendra, Marburg, MERS, Hemorrhagic Fever Virus, and Crimean-Congo. No language limits were applied. The final search was completed on 20.06.2015. Of 1960 articles, title searches excluded many irrelevant articles, yielding 303 articles read in full. Of these, 179 are referenced in this study. RESULTS: Serum therapy was first used in the 1890s against diphtheria. Early preparation techniques yielded products contaminated with reactogenic animal proteins. The introduction of enzymatic digestion, and purification techniques substantially improved their safety profile. The removal of the Fc fragment of antibodies further reduces hypersensitivity reactions. Clinical studies have demonstrated the efficacy of polyclonal antibodies against various infections, toxins and venoms. Products are being developed against infections for which prophylactic and therapeutic options are currently limited, such as avian influenza, Ebola and other zoonotic viruses. CONCLUSIONS: Polyclonal antibodies have been successfully applied to rabies, envenomation and intoxication. Polyclonal production provides an exciting opportunity to revolutionise the prognosis of both longstanding neglected tropical diseases as well as emerging infectious threats to humans.

History and Practice: Antibodies in Infectious Diseases.

Antibodies and passive antibody therapy in the treatment of infectious diseases is the story of a treatment concept which dates back more than 120 years, to the 1890s, when the use of serum from immunized animals provided the first effective treatment options against infections with Clostridium tetani and Corynebacterium diphtheriae. However, after the discovery of penicillin by Fleming in 1928, and the subsequent introduction of the much cheaper and safer antibiotics in the 1930s, serum therapy was largely abandoned. However, the broad and general use of antibiotics in human and veterinary medicine has resulted in the development of multi-resistant strains of bacteria with limited to no response to existing treatments and the need for alternative treatment options. The combined specificity and flexibility of antibody-based treatments makes them very valuable tools for designing specific antibody treatments to infectious agents. These attributes have already caused a revolution in new antibody-based treatments in oncology and inflammatory diseases, with many approved products. However, only one monoclonal antibody, palivizumab, for the prevention and treatment of respiratory syncytial virus, is approved for infectious diseases. The high cost of monoclonal antibody therapies, the need for parallel development of diagnostics, and the relatively small markets are major barriers for their development in the presence of cheap antibiotics. It is time to take a new and revised look into the future to find appropriate niches in infectious diseases where new antibody-based treatments or combinations with existing antibiotics, could prove their value and serve as stepping stones for broader acceptance of the potential for and value of these treatments.

[Behring's personal papers--Behring's lives]. / Behrings Nachlässe--Behrings Biographien.

The article wants to show the connection between the enriched personal papers of Emil von Behring (1854-1917) in the Behring archives in Marburg (established in 1927) and the history of the first biography of the scientist, which was published by Heinz Zeiss and Richard Bieling during Nazi era in 1940. One focus is placed on Behring's widow Else von Behring (1876-1936), who was active in arranging Behring's papers in proper order and in searching a biographer of her husband's life. The paper also presents new discoveries from the Behring Works archives in Marburg which show Behring--founder of the serum therapy and first winner of the Nobel Prize for medicine in 1901--as an entrepreneur who was fighting for control and influence in the field of science and of business: maybe another narration of Behring's life.

From Bretonneau to therapeutic antibodies, from specificity to specific remedies, Saint-Cyr-Sur-Loire, France, November 19, 2012.

Held on November 19, 2012 in Saint-Cyr-sur-Loire, France, the symposium "From Bretonneau to therapeutic antibodies, from specificity to specific remedies" focused on the historical development of antibodies as therapeutics, with an emphasis on the seminal work of the French physician Pierre-Fidèle Bretonneau (1778-1862). The morning session was devoted to discussion of the evolution of the concept of specificity in medicine, which started with an epistemological definition. The contributions of Bretonneau to the emergence of the concept of specificity, notably with his studies on diphtheria, and the subsequent development of antidiphtheric serotherapy in Europe during the period 1894-1898 were then presented in detail. The afternoon session began with a presentation on the role of French physiologists during the years 1860-1890 in establishing the basic concepts of specific immunity and the principles of serotherapy. The history of antivenom serotherapy, particularly its discovery by Césaire Phisalix, and the development of antilymphocyte globulins as successful transplantation drugs were then discussed. The symposium ended with the inauguration of a stele representing Bretonneau, who lived in Saint-Cyr-sur-Loire and died 150 y ago.

Una perspectiva heterodoxa de la historia de los medicamentos. Dinámicas de inclusión-exclusión de los sueros antituberculosos Ravetllat-Pla en la España del primer tercio del siglo XX / A heterodox perspective on the history of drugs. Inclusionexclusion dynamics of the Ravetllat-Pla anti-tuberculosis serum in the first third of the 20th century

En 1924, momento histórico de auge de la tuberculosis en España, fue fundado el Instituto Ravetllat-Pla con el fin de producir y comercializar un suero antituberculoso fundamentado en una teoría propuesta por el veterinario Joaquim Ravetllat i Stech (1872-1923). La nueva teoría etiopatológica de la tuberculosis propuesta por Joaquim Ravetllat evidenciaba la variabilidad ontológica del bacilo de Koch proponiendo nuevas formas bacterianas que no habían sido descritas. El tisiólogo catalán Ramon Pla i Armengol (1880-1958) encontró en la teoría de Joaquim Ravetllat fundamento a los síntomas clínicos que observaba en sus pacientes por lo que continuó la investigación en alianza con el veterinario. Esta teoría científica fue considerada heterodoxa por la ciencia oficial de la época lo que condujo al establecimiento de un espacio de exclusión en el que el Instituto adoptó la identidad de heterodoxo. Como reacción a la exclusión el Instituto generó otro espacio de inclusión en el que, a través del éxito comercial de sus productos farmacéuticos, su refutada teoría científica fue legitimada y validada socialmente. En el presente artículo, se propone que la consideración de los medicamentos como productos comerciales permite evidenciar la participación activa de los distintos usuarios del suero Ravetllat-Pla en su construcción, reconceptualización y legitimación social. Además, desde las dinámicas de inclusión y exclusión, esta investigación contribuye al entendimiento de los procesos de legitimación del conocimiento desde de la heterodoxia científica (AU)

In 1924, a historically peak time for tuberculosis in Spain, the Ravetllat-Pla Institute was established with the aim of producing and commercializing an anti-tuberculosis serum and researching the variability of the bacteria implicated in this infection. This bacterial form, proposed by Joaquim Ravetllat in the first decade of the 20th century, led to the formulation of a new etiological-pathologic theory of tuberculosis, which upheld the drugs produced by the Institute and was considered heterodox by the official science of the time. The Catalan medical and political network established a space of exclusion leading to the marginalization of the Institute, which, by strengthening its heterodox identity, generated another space of inclusion. In this space, its refuted scientific theory could be socially legitimated and validated through the commercial success of its pharmaceutical products. In this paper, we suggest that the consideration of medicines as commercial products illustrates the active participation of the different users of the Ravetllat-Pla serum in its social construction, re-conceptualization and legitimization. Moreover, from the theoretical framework of inclusion-exclusion dynamics, this research contributes to understanding the processes of knowledge legitimatization by scientific heterodoxy

Therapeutic monoclonal antibodies.

Over a hundred years has passed since the discovery of the "magic bullet" serum therapy by Kitasato and Behring, the first ever therapeutic use of antibodies. More than 80 years later, the investigation of immunoglobulin structure and function and the development of cell and molecular biology introduced the production of monoclonal antibodies (MoAbs). In the 35 years since the first process for creating MoAbs was introduced, they have remained the centerpiece of the growing biotechnology and pharmaceutical industry. Herein, I review the history, development, and clinical settings of therapeutic MoAbs that have had a significant impact on life-saving medicine.

The Nobel Prize laureate - father of anaphylaxis Charles-Robert Richet (1850-1935) and his anticancerous serum.

Professor of physiology Charles-Robert Richet, winner of the Nobel Prize in 1913, is best known for his work on anaphylaxis. However, with his collaborator Jules Héricourt studied the effects of antibody treatment and made the very first attempts to fight cancer with serotherapy. Being versatile, Richet contributed in neurology, psychology and was also a poet, playwrighter, pacifist and pioneer in aviation.

[Passive immunotherapy today: brief history]. / L'immunothérapie passive aujourd'hui: bref historique.

Brief recall of the history of passive immunotherapy and its current importance.

[The use of passive rabies immunotherapy: from the past to the future]. / L'immunothérapie antirabique passive d'hier et d'aujourd'hui.

Rabies is a fatal disease transmitted by infected animals by bite, scratch, licking on broken skin or contamination of mucosis by saliva. The regimen of post-exposure prophylaxis for people not previously vaccinated, that is currently recommended by WHO, consists of a combination of wound cleaning, active immunization and passive immunization when the exposure is of category 3. Most of the products available on the market, in particular human rabies immunoglobulins, highly purified equine rabies immunoglobulins and the derived F(ab')(2) fragments, are now characterized by high potency and safety. Although the interest of passive anti-rabies immunization was first demonstrated in the first half of the 20th century, there is still an inadequate supply of these products to the target populations mostly in developing countries. Therefore, it is urgent to set-up training and information actions for healthcare personnel on the need to use passive immunotherapy and the lack of adverse effects of the related products. For the future, we hope that a scale up of production and a lower price will improve the accessibility to these products. The development of new products based on monoclonal antibodies and molecular biology, and which may be cheaper, is promising.