The Science

History

Evolution has provided a mechanism to protect newborns of every vertebrate species – antibodies. These are passed from mothers, who have survived many infections, to newborns either via the placenta or milk. Louis Pasteur was the first to use antibodies to prevent a fatal disease – rabies. Beginning in the 19th century, antibodies were used to prevent tetanus and diphtheria. In 1960, antibodies were found to be carried on immunoglobulin G (IgG) molecule. This resulted in the production of concentrated IgG antibodies as a byproduct of blood donations. For several decades, this product, hyper-immune gamma globulin (IGG) prevented disease for which there were no vaccines.  In the 1950s, just before the Salk vaccine came on the market, William McD Hammon at the University of Pittsburgh used to IGG to prevent polio in trials involving hundreds of thousands of children in a blinded efficacy trial that successfully blunted attack rates of paralysis during epidemics of poliomyelitis.6 IGG has been licensed in the United States to prevent hepatitis A and B in travelers with special used in  persons exposed to rabies, chickenpox, measles, tetanus, respiratory syncytial virus or cytomegalovirus.

RSV Antibody Example

Respiratory syncytial virus (RSV), an orthopneumovirus, is a negative strand enveloped RNA virus that causes human respiratory disease resulting in a severe and fatal disease in infants.  Worldwide, this is one of the most important viral respiratory diseases of humans. For reasons not fully understood, it has not been possible to make a safe and effective RSV vaccine. Instead, in 1996, protective polyclonal or monoclonal antibodies (Mab) from immune serum donors were licensed by the US FDA. The commercial Mab product, palivizumab, is highly effective in preventing premature infants from fatal RSV.  Inactivated RSV and coronavirus vaccines can produce an altered state that reduces vaccine efficacy.   There is good reason to believe that a corresponding preventive product for COVID 19 – monoclonal or polyclonal antibodies – will similarly protect high risk persons from severe or fatal disease.

Now

Millions of Americans have survived COVID 19 infections and now circulate antibodies. Can’t we use their antibodies to prevent infection?  We can. COVID 19 antibodies have been shown to protect animals from infection and disease. Immune globulins prepared from convalescent donors can provide short term protection to caregivers and healthcare workers and, crucially, to those at high risk of severe or fatal COVID 19.   Specialized protective monoclonal antibodies (MAb) also are obtained from disease survivors. These are being produced at commercial scale by several reputable pharmaceutical companies. The use of IGG or MAb to protect vulnerable persons and essential workers is an essential way to lessen the terrible burden of COVID 19. 

 Science Publications

Here are some of the most important and relevant recent scientific publications on research and development of monoclonal antibodies and hyper-immune globulin for: 

  1. treatment of other diseases in recent years; and
  2. rapid development efforts in 2020 to address Covid-19.

 New England Journal of Medicine Updates

New England Journal of Medicine,  January 21, 2021.   Published an overview and two important updates focused on the efficacy and safety of Monoclonal Antibodies.

Progress in the Treatments of Covid-19

Global Virus Network, November 25, 2020.   A review of all available treatments based on the findings of clinical trials, and recommendations for public health and policy makers. 

Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults

New England Journal of Medicine,  January 6, 2021.  This study is another clinical study that demonstrates what history, experience and other studies have demonstrated was already known to be very likely:  antibodies, if given prophylactically prior to exposure or shortly after infection, are a highly effective treatment which will reduce hospitalizations and deaths.

COVID research updates: Immune responses to coronavirus persist beyond 6 months

Nature, November 20, 2020:  Nature wades through the literature on the new coronavirus — and summarizes key papers as they appear.

Bridging the Gap at Warp Speed — Delivering Options for Preventing and Treating Covid-19

New England Journal of Medicine, Nov. 12, 2020:   An article by the Director and chief scientists at Operation Warp Speed.  Explains that while much attention has been directed to OWS’s goal of delivering substantial quantities of safe and effective vaccines by early 2021, the initiative also aims to combat Covid-19 by improving the use of existing therapies and providing additional treatment options as a way to ameliorate the pandemic as we wait for the U.S. population to be fully immunized.   Includes descriptions and updates on mAbs and other antibody-based approaches as of that date.

SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19

New England Journal of Medicine, Oct. 28, 2020:   The results of a preplanned interim analysis as of September 5, 2020 of (at that time) the ongoing phase 2 trial involving outpatients with recently diagnosed mild or moderate Covid-19 for Eli Lilly’s neutralizing antibody LY-CoV555.    Virus-neutralizing monoclonal antibodies are predicted to reduce viral load, ameliorate symptoms, and prevent hospitalization.   In this study, 452 patients were randomly assigned to receive a single intravenous infusion of neutralizing antibody LY-CoV555 in one of three doses (700 mg, 2800 mg, or 7000 mg) or placebo and evaluated the quantitative virologic end points and clinical outcomes.  

Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms

Science 24 Sep 2020.  Researchers from the University of Washington, the Institute Pasteur in Paris, and Vir Biotechnology in Switzerland have developed an ultrapotent cocktail of antibodies from recovered COVID-19 patients has been shown to recognize and lock down the infection machinery of the pandemic coronavirus and keep it from entering cells. Each of the antibody types performs these overlapping tasks slightly differently.
 

Antibody “Cocktail” Could Offer Potent Treatment, Prevention of COVID-19

AJMC, July 23, 2020:  Writing in Nature, scientists found the antibodies fell into 2 distinct groups, targeting different regions of the viral spike. Thus, they say, the battle against coronavirus disease 2019 (COVID-19) could be opened on separate fronts, much like the approach Ho and others have studied in HIV and some forms of cancer.

 

Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike 

Nature, July 22, 2020.  Research directed by David Ho, MD, scientific director of the Aaron Diamond AIDS Research Center and professor of medicine at Columbia University Vagelos College of Physicians and Surgeons confirmed that their purified, strongly neutralizing antibodies provide significant protection from SARS-CoV-2 infection in hamsters, and they are planning further studies in other animals and people.  These antibodies could be produced in large quantities by pharmaceutical companies to treat patients, especially early in the course of infection, and to prevent infection, particularly in the elderly.

COVID-19 and SARS Coronavirus 2: Antibodies for the Immediate Rescue and Recovery Phase

Frontiers of Immunology, May 29, 2020.  An overview published in  of recent developments in trials with monoclonal human antibodies, explaining how epidemiology can and should be applied with this tool to immediately control the damage from COVID-19 and manage a transition to normalcy.

COVID-19: The Need for Immunoprevention at Industrial Scale

The American Journal of Tropical Medicine and Hygiene, Volume 102, Issue 6, 3 Jun 2020.    A call to action to focus resources and appoint a national czar to direct efforts to complete trials and scale the production of antibody-based drugs to combat COVID-19.

An Urgent Need for “Common Cold Units” to Study COVID-19

The American Journal of Tropical Medicine and Hygiene, Volume 102, Issue 6, 3 Jun 2020.  To bring protective products on line in a matter of months to meet the current emergency, affected nations should establish national coronavirus clinical units.

COVID 19 Vaccines: Should we fear ADE?

Journal of Infectious Disease. 2020 Aug 12;jiaa518.  A survey of research that shows that there is no indication of ADE risk associated with COVID-19.

Related Research Papers

Alexander D. Douglas & Adrian V. S. Hill.  Immunological considerations for SARS-CoV-2 human challenge studies.  Nature Reviews Immunology volume 20, pages 715–716(2020)

Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol 2020;38:1-9.

Casadevall, Pirofski L. The convalescent sera option for containing COVID-19. Journal of Clinical Investigation 2020;130: https://doi.org/10.1172/JCI138003.

Mair-Jenkins J, Saavedra-Campos M, Baillie JK, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis 2015;211:80-90.

Young MK, Nimmo GR, Cripps AW, Jones MA. Post-exposure passive immunisation for preventing measles. Cochrane Database Syst Rev 2014:Cd010056.

Janeway CA. Use of Concentrated Human Serum gamma-Globulin in the Prevention and Attenuation of Measles. Bulletin of the New York Academy of Medicine 1945;21:202-22.

Rinaldo CR, Jr. Passive immunization against poliomyelitis: the Hammon gamma globulin field trials, 1951-1953. American journal of public health 2005;95:790-9.

Krugman S, Ward R. Infectious hepatitis: current status of prevention with gamma globulin. The Yale journal of biology and medicine 1961;34:329-39.

Eyal N, Lipsitch M, Smith PG. Human challenge studies to accelerate coronavirus vaccine licensure. J Infect Dis 2020.

Harcourt J, Tamin A, Lu X, et al. Severe Acute Respiratory Syndrome Coronavirus 2 from Patient with 2019 Novel Coronavirus Disease, United States. Emerg Infect Dis 2020;26.

Sabin AB, Schlesinger RW. Production of immunity to dengue with virus modified by propagation in mice. Science 1945;101:640-2.

Kirkpatrick BD, Whitehead SS, Pierce KK, et al. The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model. Sci Transl Med 2016;8:330ra36.

Matuschewski K, Borrmann S. Controlled Human Malaria Infection (CHMI) Studies: Over 100 Years of Experience with Parasite Injections. Methods Mol Biol 2019;2013:91-101. 

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