Global Virus Network (GVN) Presents Doherty Institute Director, University of Melbourne Professor Sharon Lewin with the Robert C. Gallo Award for Scientific Excellence and Leadership in Medical Virology

Baltimore, Maryland, USA, September 22, 2020: The Global Virus Network (GVN), comprising foremost experts around the world in every class of virus-causing disease in humans and some animals, today presented Doherty Institute Director, University of Melbourne Professor Sharon Lewin with the Robert C. Gallo Award for Scientific Excellence and Leadership in Medical Virology  Presented today at the GVN Special Annual Meeting, Professor Lewin was selected for her outstanding clinical virology research and clinical trials, her leadership in Australian medical science as Director of the Doherty Institute, and her leadership in the GVN.

Professor Lewin has an international reputation in the field of HIV latency and eradication and immune reconstitution and HIV-hepatitis B virus co-infection.

In 2020 she has worked tirelessly at the helm of the Doherty Institute which has been at the forefront of Australia’s response to the COVID-19 pandemic.

Professor Lewin said it was an incredible honour to be presented with the Robert Gallo Award.

“The GVN is among other things, dedicated to identifying, research, combatting and preventing current and emerging pandemic viruses, it’s reason for being has never been so relevant. It’s a privilege to receive the Robert Gallo Award, and to be so closely linked as a GVN Center of Excellence Director,” Professor Lewin said.

The Doherty Institute is one of 57 GVN global Centers of Excellence, which Professor Lewin co-leads with Professor Damian Purcell and Professor Peter Revill.

The award is named after GVN Co-Founder and International Scientific Advisor, Professor Robert Gallo, who is most widely known for his co-discovery of HIV as the cause of AIDS and the development of the HIV blood test.

“Sharon Lewin is an international leader in clinical research,” said Professor Robert C. Gallo, co-founder of GVN and the current Director of the Institute of Human Virology at the University of Maryland School of Medicine.  “Additionally, she has been, and will continue to be, a medical science thought leader for the field of clinical virology and a powerful presence in Australia and globally as a scientific leader of the Doherty Institute, quickly establishing this GVN Center as one of excellence. I know all in the GVN are very happy and proud to honor her.”

“I congratulate Sharon Lewin for such a well-deserved award,” said GVN President Professor Christian Bréchot.  “Indeed, this recognizes her major scientific achievements and her full commitment to both the fight against HIV and support for the Global Virus Network.”

About the Global Virus Network (GVN)
The GVN is essential and critical in the preparedness, defense and first research response to emerging, exiting and unidentified viruses that pose a clear and present threat to public health, working in close coordination with established national and international institutions. It is a coalition comprised of eminent human and animal virologists from 57 Centers of Excellence and 10 Affiliates in 33 countries worldwide, working collaboratively to train the next generation, advance knowledge about how to identify and diagnose pandemic viruses, mitigate and control how such viruses spread and make us sick, as well as develop drugs, vaccines and treatments to combat them. No single institution in the world has expertise in all viral areas other than the GVN, which brings together the finest medical virologists to leverage their individual expertise and coalesce global teams of specialists on the scientific challenges, issues and problems posed by pandemic viruses. The GVN is a non-profit 501(c)(3) organization. For more information, please visit www.gvn.org and follow on Twitter @GlobalVirusNews.

Current Status of COVID-19 Vaccine Development

As the COVID-19 pandemic expands, interests in the progress of vaccine development are intensifying. Despite an unprecedented rate of progress, it is still uncertain when a safe, effective vaccine will be available for wide distribution to the public. Successful vaccine development goes through a series of stages, from animal studies for the evaluation of its protective immunogenicity to phase 1 (safety and antibody production), phase 2 (safety and immunogenicity by including a placebo group), and phase 3 (verification of safety, and efficacy in, a large population group) clinical trials. This is obviously a long, drawn out process, yet it is necessary to ensure the efficacy and safety of vaccines. In addition, it takes very high numbers of participants to generate meaningful and significant statistics to prove vaccine protection. This makes these trials expensive and their enrollment process lengthy, but phase 3 trials are clearly necessary, and are the most important step for its approval.

Immunogenicity studies are especially critical because there is not yet a clear understanding of what constitutes a protective immune response. Neutralizing or IgG antibody titers against the spike (S) protein do not seem to correlate inversely with disease severity, although it may be that rapid expression of such antibodies would be protective. Another issue is that neutralizing antibodies may only last a few months. However, immune memory cells may facilitate rapid production of such antibodies after infection. Even less is known about the role or relevance of T cell responses in protection. With all these caveats in mind, we will discuss nine candidate vaccines that are in the most advanced stages of development.  Most, but not all, are focused exclusively on the S protein, in large part because it is the target of neutralizing antibodies.

There are currently two vaccines in the late stage of development that depend upon injection of mRNA encoding the spike protein or portions including the receptor binding domain (RBD) of the S protein. These have an advantage of being easy to produce but have the disadvantage of needing to be stored at 4°C, requiring a cold chain supply, thus presenting difficulties for use in low-income countries. These two vaccines are produced by Moderna and Pfizer/BioNTech. Its limitations associated with the intracellular instability and inefficient delivery of mRNA have been addressed by chemically modifying the RNA and encapsulating it in lipid nanoparticles.

The Moderna vaccine (mRNA-1273) and one of the two Pfizer vaccines (BNT162b2) encode prefusion conformation of the S proteins. The other Pfizer vaccine (BNT162b1) encodes trimerized soluble S protein receptor binding domains on a peptide linker scaffold. The Moderna vaccine was protective in rhesus macaques. Human phase 1 trial results were reported in June by demonstrating its safety and immunogenicity with induction of binding and neutralizing antibodies equivalent to the levels that are seen in natural infection. The antibody levels persisted until at least day 43 post-vaccination. A phase 2 trial with 600 participants was begun in June. Phase 3 trials to determine efficacy and safety were initiated in August and will have 30,000 participants.

Pfizer decided to concentrate on BNT162b2, as it is equally immunogenic to BNT162b1 but generates fewer side effects. There do not appear to be any reports of trials with non-human primates. Three phase 1 trials showed that both vaccines elicited binding and neutralizing antibodies, but lesser side effects led to the selection of BNT162b2 for phase 3 trials (Publication 1, Publication 2). Trials began in August and, as with the Moderna trials, aim to enroll 30,000 participants.

The other nucleic acid-based vaccine, developed by Inovio (INO-4800), is comprised of DNA encoding the S protein. The DNA vaccine, unlike the mRNA vaccines, is stable at room temperature. The DNA is injected intramuscularly and then electroporated into cells by a hand-held device delivering a brief electric pulse.  The vaccine was partially protective in rhesus monkeys against a viral challenge three months after vaccination as judged by a reduction in viral titers. Inovio claims that antibody and/or T cell responses were induced after two doses of the vaccine in 94% of the 40 participants in Phase 1 trials, but they have not yet published the results. They are scheduling Phase 3 trials for September.

The Novavax vaccine candidate, NVX-CoV2373, is a full-length stabilized spike protein produced in insect cells and formulated into a lipid nanoparticle. Reports from a phase 1-2 trial showed that binding and neutralizing antibodies were elicited(1). Antibody levels were greatly increased, and T cell activities (especially Th1) were induced when NVX-CoV2373 was combined with a saponin-based adjuvant. Phase 3 trials are planned for late 2020.

There are currently three late stage vaccines that use adenoviral vectors to deliver their payloads to express the S protein. These include AstraZeneca/University of Oxford, which uses a chimpanzee adenovirus originally isolated from a chimp stool sample, Johnson and Johnson/Janssen (adeno26) and Cansino/Beijing Institute of Biotechnology (adeno5), the two latter of which are human adenoviruses. All three adenoviral vectors have been genetically modified to render them incapable of self-replication. The reasoning behind the use of a chimp adenovirus was to avoid the possibility that vaccinees previously infected by human adenoviruses would mount in an immune response against the vector, thus diminishing the efficacy of the vaccine.

The AstraZeneca vaccine, ChAdOx1 nCoV-19, was shown to partially protect rhesus macaques from viral challenge(2). Out of 6 vaccinated animals, none showed signs of pneumonia or lung pathology, while 3 of 6 controls developed interstitial pneumonia. The vaccine elicited binding and neutralizing antibodies against the S protein as well as Th1 and Th2 responses. Protection was not, however, sterilizing. Vaccinated animals had reduced viral loads in their lower respiratory tracts compared to controls, but viral loads in the nasopharynx were equivalent in both groups. A randomized phase1/2 trial with >1,000 subjects was injected with either ChAdOx1 nCoV-19 or the same vector with an unrelated antigen(3). The vaccine elicited binding and neutralizing anti-S antibodies as well as a T cell response without exhibiting serious adverse events. ChAdOx1 nCoV-19, currently in phase 3 trials, has recently been in the news because of a potential serious adverse reaction that temporarily halted the trials. A vaccinated women developed a severe spinal inflammation (transverse myelitis), which can occasionally develop following viral infections. She has since recovered, and it is not clear whether this is related to the vaccine. Trials have since resumed in Britain, but the Food and Drug Administration (FDA) has not yet approved resumption in the US. There are two ways to view this event. It could be considered to reflect the speed with which these vaccines are being developed and might be a cause for apprehension.

The Johnson and Johnson vaccine, Ad26.COV2.S, expresses a prefusion conformation of S protein (proline-stabilized S protein) in a human adeno 26 vector. In rhesus macaques, vaccinated animals developed high levels of binding and neutralizing anti-S protein antibodies and a Th1 biased T cell response(4). The authors suggested that neutralizing antibodies, but not cell-mediated immune activities, were correlative on protection. All 20 controls were infected and developed minimal disease after intratracheal and intranasal challenge. Five of six vaccinated animals were protected from detectable infection, and the sixth had a 3-4 log reduction in virus loads. Ad26.COV2.S is currently in phase 1/2 trials with 11,000 subjects that was started in June. Phase three trials are scheduled for September with 30,000 participants.

The CanSino vaccine, Ad5-S-nb2, contains a codon-optimized gene expressing the S protein. In rhesus macaques, a single dose elicited neutralizing and S protein binding antibodies and activated cell mediated immune responses after intramuscular inoculation(5). Intranasal inoculation induced antibody production but only weak cellular immunity. In an open label non-randomized trial, the vaccine was immunogenic in humans and generally well tolerated with the main adverse effect of being pain(6).  A phase 2 trial with ~600 participants confirmed immunogenicity and safety(7).

There are three vaccines, developed by Sinovac, Beijing Institute of Biological Products, and Sinopharm, that are based upon chemically inactivated whole SARS-CoV-2. These vaccines, unlike the others, contain all the viral structural proteins, and thus, might be expected to induce a wider T cell response than the other vaccines, which contain only the S protein. The Sinovac candidate, Coronavac, elicited neutralizing and binding antibodies against the S protein(8). The highest vaccine dose protected animals completely against an intratracheal challenge, and lower doses prevented severe interstitial pneumonia and resulted in greatly reduced vial loads. In a phase 1/2 trial, Sinovac claimed that 90% of the volunteers developed neutralizing antibodies and had no serious adverse effects. There was no sign of antibody-dependent enhancement within the time frame reported. Sinovac initiated phase 3 trials in Indonesia and Brazil in August and is planning another trial in Bangladesh. Another inactivated virus vaccine (BBIBP-CorV), developed by the Beijing Institute of Biological Products, induced anti-S protein binding and neutralizing antibodies in rhesus macaques and cynomolgus monkeys and protected rhesus macaques from intratracheal challenge(9). BBIBP-CorV will soon be entering human trials. Two other similarly inactivated whole vaccines, produced by Sinopharm, induced neutralizing antibodies in phase 1 trials and had no serious adverse effects(10). Phase 3 trials with this vaccine were started in July in the UAE. 

The speed of vaccine development with which this has happened is remarkable. The general take home message gleaned from an overview of these vaccines is that they induce neutralizing antibodies, stimulate T cell-mediated activity, and partially or completely protect non-human primates from infection and/or serious disease. None appear to cause an undue level of adverse events. The most pressing question is of course when one or more will be available. However, many uncertainties remain given the lack of robust clinical data. We still need to wait for finalization of phase III trials to confirm the safety and efficacy of the vaccine candidates. In particular, potential induction of antibody-dependent enhancement could be a concern. Immunogenicity of vaccine candidates are focused on the induction of neutralizing antibodies. Furthermore, they are mostly administrated by using the intramuscular route, thus limiting the induction of mucosal immunity. Intranasal immunization approach also needs to be considered. In addition, most vaccine candidates might require two doses (prime and boost vaccinations) to enhance their protective efficacy. For a global vaccination, this poses challenges financially and logistically. Therefore, we also need to consider the non-specific protective effects of live vaccines based on stimulation of innate immunity and trained innate immunity (i.e. epigenetic changes induced by live vaccines).

References

 

  1. C. Keech et al., Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine. N Engl J Med, (2020).
  2. N. van Doremalen et al., ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature, (2020).
  3. P. M. Folegatti et al., Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 396, 467-478 (2020).
  4. N. B. Mercado et al., Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques. Nature, (2020).
  5. L. Feng et al., An adenovirus-vectored COVID-19 vaccine confers protection from SARS-COV-2 challenge in rhesus macaques. Nat Commun 11, 4207 (2020).
  6. F. C. Zhu et al., Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet 395, 1845-1854 (2020).
  7. F. C. Zhu et al., Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 396, 479-488 (2020).
  8. Q. Gao et al., Development of an inactivated vaccine candidate for SARS-CoV-2. Science 369, 77-81 (2020).
  9. H. Wang et al., Development of an Inactivated Vaccine Candidate, BBIBP-CorV, with Potent Protection against SARS-CoV-2. Cell 182, 713-721 e719 (2020).
  10. S. Xia et al., Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. JAMA, (2020).

 

Global Virus Network Announces 2020 Special Annual Meeting

World-Renowned Scientists Come Together to Address COVID-19, Ramifications for Future Epidemics and Pandemics  at September 22-23 Virtual Meeting

Editors’ note: Media are invited to participate in a virtual press conference on Thursday, September 24 at 9 am ET, which will highlight key outcomes/findings of the meeting. GVN founders and session chairs will present the findings, followed by a QA session for news media. To register or learn more, email GVN-SVC@sardverb.com.

Baltimore, Maryland, USA, September 17, 2020: The Global Virus Network (GVN), a coalition of the world’s leading medical virology research centers working to prevent illness and death from viral disease, will hold its 2020 GVN Special Annual Meeting virtually September 22-23, 2020.  The current SARS-CoV-2 (COVID-19) crisis has now been ongoing for more than seven months and it is timely to investigate what went wrong, what went right, and what GVN proposes for future pandemics.  GVN, a partner of international institutions such as the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC), looks forward to providing guidance on lessons learned from this current crisis and future preparedness, particularly as we prepare for a potential second wave of SARS-CoV-2 infections.

Discussion topics will include vaccine development, therapeutics and diagnostics, as well as ensuring that scientific truth and fact prevails. This analysis will examine key pandemic response strategies, including a universal masking policy, creating a consortium to improve diagnostics and vaccines, enhancing peer reviewed processes and establishing reliable channels for information sharing. The invitation-only meeting will bring together experts in virology, epidemiology and public health, including representatives of GVN Centers of Excellence, to facilitate international collaboration and information sharing.

“There could not be a more critical time for our organization to host a special meeting as the world continues to battle the COVID-19 pandemic. We look forward to the collaborative ideas, insights, perspectives and recommendations that our Annual Meetings consistently provide, enlightening our members and the broader global scientific community and world leaders in their work addressing virus-causing diseases,” said GVN President Christian Bréchot, MD, PhD. “And at this critical time, we need shared expertise and strategies as we work together to anticipate the second wave of COVID-19 and future pandemics.”

“If there existed a collaborative, first research response such as the GVN when I was working on AIDS, we would have distributed the fast-moving scientific developments more rapidly and saved countless more lives.  COVID-19 is no different, the world should have been better prepared, and still it is not,” said Dr. Robert C. Gallo, co-founder of GVN and the current Director of the Institute of Human Virology at the University of Maryland School of Medicine. “The GVN Special Annual Meeting will give us the opportunity to determine what we must do to address the impending second wave of COVID-19 and be better prepared for the future epidemics and pandemics to come.”

The conference will include presentations by leading international scientists from nine countries representing 15 GVN Centers of Excellence. In addition to Drs. Gallo and Bréchot, presenters include:

 

  • Sharon Lewin of Doherty Institute, Australia
  • Edward Holmes of University of Sydney, Australia
  • Joaquim Segales of Irta-Cresa, Spain
  • Wim H. M. Van Der Poel of Wageningen University, Netherlands
  • Ben Cowling of the University of Hong Kong, China
  • Raymond Schinazi of Emory University Center, USA
  • David Block of Glinknik, USA
  • John Mellors of the University of Pittsburgh, USA
  • Rabindra M. Tirovanziam of Emory University, USA
  • Franco Buonaguro of the National Cancer Institute, Italy
  • Miguel Luengo-Oroz of Un Global Pulse, USA
  • Linfa Wang of the Duke-NUS Medical School, Singapore
  • Florian Krammer of Mount Sinai, USA
  • Amy Chung of University of Melbourne, Australia
  • Sophie Valkenburg of the University of Hong Kong, China
  • Konstantin Chumakov of the FDA Office of Vaccines Research and Review, USA
  • Marion Gruber of the FDA Office of Vaccines Research and Review, USA
  • Chirstine Stabel Benn of the University of Southern Denmark, Denmark
  • Mihai Netea of Radboud University, Netherlands
  • Gavin Cloherty of Abbott Laboratories, USA
  • David Scheer of Scheer & Company, USA
  • Mark Parrington of Sanofi, USA
  • Ab Osterhaus of TiHo Hannover, Germany
  • Matthew Frieman of the University of Maryland School of Medicine, USA
  • Gene Morse of the University of Buffalo, USA

About the Global Virus Network (GVN)

The Global Virus Network (GVN) is essential and critical in the preparedness, defense and first research response to emerging, exiting and unidentified viruses that pose a clear and present threat to public health, working in close coordination with established national and international institutions. It is a coalition comprised of eminent human and animal virologists from 57 Centers of Excellence and 10 Affiliates in 33 countries worldwide, working collaboratively to train the next generation, advance knowledge about how to identify and diagnose pandemic viruses, mitigate and control how such viruses spread and make us sick, as well as develop drugs, vaccines and treatments to combat them. No single institution in the world has expertise in all viral areas other than the GVN, which brings together the finest medical virologists to leverage their individual expertise and coalesce global teams of specialists on the scientific challenges, issues and problems posed by pandemic viruses. The GVN is a non-profit 501(c)(3) organization. For more information, please visit www.gvn.org. Follow us on Twitter @GlobalVirusNews.

Media Contacts:

Sard Verbinnen & Co
Kelly Kimberly/Kelly Langmesser
GVN-SVC@sardverb.com
+1.212.687.8080

GVN
Nora Samaranayake
410-706-1966
nsamaranayake@gvn.org

 

 

Abbott partners with the Global Virus Network on a new coalition to prepare for future pandemics

In late 2019, a group of infectious disease experts had an idea— to create a coalition among leaders in the public and private sectors that could help prepare for how the global health community responds to emerging pandemics and collaborate to end major viral pandemics.

As the initial program formed between Abbott and Global Virus Network (GVN) – a global coalition of medical virologists – the group quickly realized they would be developing a blueprint for pandemic preparedness, while in the middle of one.

“We are seeing first-hand the urgent need for collaboration when it comes to a novel virus that becomes a pandemic,” says Christian Bréchot, M.D., Ph.D., and president of the Global Virus Network (GVN). “By having this coalition in place, we are essentially creating the instructional manual for how we respond to emerging pandemics, while also creating the vehicle to do so.”

A global virus coalition

The GVN Corporate Centers of Excellence Coalition was first created in late 2019 as a way to bring together the world’s foremost virologists and prominent companies to catalyze and facilitate the development, evaluation and testing of diagnositcs, therapeutics, treatments and vaccines for viral epidemics and pandemics that pose a threat to public health.

As a leader in infectious disease testing and blood screening, Abbott joined as the inaugural member of the coalition.

“We know that every day matters when it comes to responding to a pandemic, which is why collaboration and preparedness are critical,” said Gavin Cloherty, Ph.D., head of Infectious Disease Research, Diagnostics, Abbott. “With this partnership, we are creating a SWAT team of highly trained scientists to share knowledge, techniques and innovative tests and technologies to better understand both existing and emerging viruses.”

The collaboration with GVN plans to focus on three initial areas:

  • Strengthening preparedness
  • Sharing research on known pathogens and emerging pathogens
  • Providing insights on the potential impact of this research

Collaboration during the COVID-19 pandemic

In the early weeks of the pandemic, Abbott brought together a team of its scientists to develop diagnostic and antibody tests to detect the virus and the antibodies that develop after an infection.

One of the key elements for developing these tests were virus samples to ensure the accuracy of our test. Through the Corporate Centers of Excellence program, Abbott collaborated with GVN to identify additional virus samples in different patient populations and has worked with GVN to determine new locations to conduct research.

The coalition is also developing the framework to collaborate and share research on the COVID-19 (SARS-CoV-2 ) virus. Abbott and GVN are establishing a SARS-CoV-2 biobank – or repository that stores biology samples – to study and validate antibody tests.

Planning for the future

From Smallpox, to HIV or the latest efforts for COVID-19, history has shown the impact infectious diseases can have and the need to stay ahead of emerging viruses.

The Centers of Excellence will take learnings developed for the fight against COVID-19 to prepare for future pandemics.

“In the early days of the pandemic, data-sharing was critical to helping the research community understand the virus. We can take the infrastructure from our SARS-CoV-2 biobank in development and use it as a template for future emerging viruses,” said Cloherty.

By developing an integrated global network of scientists and industry leaders, the healthcare community can work together to help in the fight against our current pandemic and quickly respond to future infectious disease outbreaks.

 

About the Global Virus Network (GVN)

The Global Virus Network (GVN) is essential and critical in the preparedness, defense and first research response to emerging, exiting and unidentified viruses that pose a clear and present threat to public health, working in close coordination with established national and international institutions. It is a coalition comprised of eminent human and animal virologists from 55 Centers of Excellence and 10 Affiliates in 33 countries worldwide, working collaboratively to train the next generation, advance knowledge about how to identify and diagnose pandemic viruses, mitigate and control how such viruses spread and make us sick, as well as develop drugs, vaccines and treatments to combat them. No single institution in the world has expertise in all viral areas other than the GVN, which brings together the finest medical virologists to leverage their individual expertise and coalesce global teams of specialists on the scientific challenges, issues and problems posed by pandemic viruses. The GVN is a non-profit 501(c)(3) organization. For more information, please visit www.gvn.org. Follow us on Twitter @GlobalVirusNews

 

GVN MEDIA CONTACT
Nora Samaranayake
Phone:  410-706-1966
Email:    nsamaranayake@gvn.org

 

COVID-19 Vs. Influenza: Influenza Vaccination Amid COVID-19 Pandemic

Severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), a highly contagious virus, emerged in 2019 from Wuhan, China (1). It rapidly spread around the world causing a novel acute respiratory disease, coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) declared COVID-19 a pandemic on March 11, 2020. Consequently, the current COVID-19 pandemic impacts global health and economies to unprecedented levels. As of August 17, 2020, over 21,760,000 cases have been confirmed in more than 188 countries, with over 776,580 deaths, and growing daily. The spectrum of disease with SARS-CoV-2 ranges from asymptomatic infection to severe, often fatal disease. Patients with mild disease (80%) have fever, cough, sore throat, loss of smell, headache, and body aches (2). A surge of COVID-19 patients resulted in enormous challenges for capacity and patient flow in hospitals and health care systems globally. Currently, we have limited interventional strategies in curbing COVID-19, and attention has been focused on the progress in the development of vaccines and therapeutics since the beginning of pandemic. Despite the progress, one cannot exclude that the virus would be continuously circulating as a seasonal virus even after the availability of a vaccination program.

Seasonal influenza is a major cause of morbidity, mortality, resulting in a burden on  healthcare services globally every year. According to the WHO, up to 650,000 deaths are associated with seasonal influenza respiratory infections annually. In the Northern Hemisphere, the 2020-2021 influenza season will coincide with the continued circulation of SARS-CoV-2. The nature of disease similarity between COVID-19 and influenza is cause for great concern. In addition, SARS-CoV-2 and influenza viruses have similar transmission characteristics. The two viruses are spread by contact and airborne transmission. The incubation period for influenza is short, typically 1–2 days, whereas for SARS-CoV-2, it is 4.5–5.8 days (2). The basic reproductive rate (R0, the average number of secondary transmissions from one infected person) for SARS-CoV-2 is estimated to be 2·5 (range 1·8–3·6) compared with 2·0–3·0 for the 1918 influenza pandemic, 1·5 for the 2009 influenza pandemic, and 1.3 for seasonal influenza viruses (3, 4). COVID-19 mortality risk has been highly concentrated at old ages (> 65 years old) and those, in particular, males, with underlying medical conditions (called co-morbidities), including hypertension, diabetes, cardiovascular disease, and immunocompromised states (2). Furthermore, SARS-CoV-2 can also infect younger individuals. In particular, children have shown to be susceptible to infection (5). Although most of the infections run a rather benign course, some children may develop severe primary and unique secondary inflammatory complications of infection, including multisystem inflammatory syndrome of children (6). Indeed, while children comprise 22% of the U.S. population, recent data show that 7.3% of all cases of COVID-19 in the U.S. reported to the Centers for Disease Control and Prevention (CDC) were among children (as of August 3rd, 2020). The number and rate of cases in children in the U.S. have been steadily increasing from March to July 2020, even though the incidence of SARS-CoV-2 infection in children is known to be underrated due to a lack of widespread testing. Opening schools in many locations might change a dynamic of transmission of SARS-CoV-2 and COVID-19 cases among children. Similar to COVID-19, influenza-associated excess mortality in elderly individuals related to a range of other chronic health conditions, including cardiovascular causes, diabetes, neoplasms and renal disease (2). In contrast to COVID-19, children are believed to have the highest rates of infection and complications arising from influenza, thus leading to high rates of excess outpatient visits, hospital admissions and antibiotic prescriptions (7). Infections among children can also drive influenza epidemics due to their increased susceptibility to infection and greater contribution to the spread of virus in the community.

Vaccination can be the most efficient and effective measures in controlling the current COVID-19 pandemics. Researchers are developing more than 170 vaccines against the coronavirus, and 47 vaccines are in human trials. In contrast, annual influenza vaccination is available with inactivated influenza vaccines, recombinant influenza vaccine, and live attenuated influenza vaccine. This the main public health intervention in reducing the burden of disease (8). The WHO has recognized some priority target groups for annual influenza vaccination, including pregnant women, children aged 6 months to 5 years, the elderly, subjects with specific chronic conditions, healthcare workers, and international travelers (9). However, influenza vaccination rates among children aged 6 months to 17 years remain low compared with other routinely recommended childhood vaccines. In-plan vaccination coverage during the 2016–17 season was 67.7% in infants (born 2015), 49.5% in toddlers (born 2012–2014), 35.0% in school-aged children (born 2004–2011), and 22.3% in teenagers (born 1999–2003) (10). Like vaccination coverage, vaccination opportunities decreased with age. Along with continued efforts to reduce missed opportunities, effective strategies to bring children to their doctor for annual influenza vaccination are needed, particularly for older children. Among adults, influenza vaccination coverage (≥18 years) was 45.3% in the U.S. during 2018–19 influenza season (11).

The information regarding COVID‐19 and influenza coinfection is limited. Unless screening patients with COVID‐19, the coinfection remains undiagnosed and underestimated. The severity of disease resulting from the co-infections varies by causing a more severe course with a fatal outcome or mild illness (12). Although this needs to be further evaluated, influenza immunization for high-risk groups can reduce the possibility of influenza infection and co-infection with SARS-CoV-2 and complications associated with diagnostics and antiviral treatment. A COVID-19 infection prediction model has also shown that influenza vaccines could reduce COVID-19 infection risk (13). This will also alleviate burden on the health care system by avoiding an overload of health services and hospitals associated with influenza infections (i.e., outpatient illnesses, hospitalizations, and intensive care unit admissions). Influenza vaccine is safe for elderly and children with a proven record over the past 50 years (7). Therefore, influenza vaccination can be a critical component of response to the COVID-19 pandemic. However, there has been a prediction that the COVID-19 pandemic could decrease influenza vaccination, since the pandemic resulted in a 38 percent drop in consumer spending on health care and loss of health insurance (14). In response, CDC already arranged for an additional 9.3 million doses of low-cost flu vaccine for uninsured adults, up from 500,000. The agency expanded plans to reach out to minority communities. It is uncertain how this upcoming influenza season will evolve under the current circumstance. In general, taking an influenza vaccine can be a good preventive strategy for public health.

 

Readers’ Comments are Welcome

 

References

  1. 2020. Rolling updates on coronavirus disease (COVID-19). July 31, 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen.
  2. Subbarao K, Mahanty S. Respiratory Virus Infections: Understanding COVID-19. Immunity. 2020;52(6):905-909. doi:10.1016/j.immuni.2020.05.004.
  3. Petersen E, Koopmans M, Go U, Hamer DH, Petrosillo N, Castelli F, Storgaard M, Al Khalili S, Simonsen L. Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics. Lancet Infect Dis. 2020 Jul 3;20(9):e238–44. doi: 10.1016/S1473-3099(20)30484-9.
  4. Biggerstaff, M., Cauchemez, S., Reed, C. et al. Estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: a systematic review of the literature. BMC Infect Dis 14, 480 (2014). https://doi.org/10.1186/1471-2334-14-480
  5. Han MS, Choi  EH, Chang  SH,  et al.  Clinical characteristics and viral RNA detection in children with coronavirus disease 2019 in the Republic of Korea.   JAMA Pediatr. Published online August 21, 2020. doi:10.1001/jamapediatrics.2020.3988.
  6. Feldstein LR, Rose  EB, Horwitz  SM,  et al; Overcoming COVID-19 Investigators and the CDC COVID-19 Response Team.  Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 2020;383(4):334-346. doi:10.1056/NEJMoa2021680.
  7. Sullivan SG, Price OH, Regan AK. Burden, effectiveness and safety of influenza vaccines in elderly, paediatric and pregnant populations. Ther Adv Vaccines Immunother. 2019 Feb 7;7:2515135519826481. doi: 10.1177/2515135519826481. PMID: 30793097; PMCID: PMC6376509.
  8. Grohskopf LA, Alyanak E, Broder KR, et al. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices – United States, 2020-21 Influenza Season. MMWR Recomm Rep. 2020;69(8):1-24. Published 2020 Aug 21. doi:10.15585/mmwr.rr6908a1.
  9. World Health Organization (WHO). Vaccines against influenza WHO position paper – November 2012. Wkly. Epidemiol. Rec. 2012, 87, 461–476.
  10. Fangjun Zhou, Megan C. Lindley, Variability in influenza vaccination opportunities and coverage among privately insured children, Vaccine, 2020, ISSN 0264-410X, https://doi.org/10.1016/j.vaccine.2020.07.061.
  11. 2019. Flu vaccination coverage, United States, 2018–19 influenza season. https://www.cdc.gov/flu/fluvaxview/coverage-1819estimates.htm#:~:text=Flu%20vaccination%20coverage%20among%20adults,than%20the%202016%E2%80%9317%20season.
  12. Co-infection with COVID-19 and influenza A virus in two died patients with acute respiratory syndrome, Bojnurd S.A. Hashemi, S. Safamanesh, M. Ghafouri, M.R. Taghavi, M.S. Mohajer Zadeh Heydari, H. Namdar Ahmadabad et al. Iran. J Med Virol (2020), 10.1002/jmv.26014
  13. Jehi L, Ji X, Milinovich A, Erzurum S, Rubin B, Gordon S, Young J, Kattan MW. Individualizing risk prediction for positive COVID-19 testing: results from 11,672 patients. Chest. 2020 Jun 10:S0012-3692(20)31654-8. doi: 10.1016/j.chest.2020.05.580.
  14. Health System Tracker. 2020. How have healthcare utilization and spending changed so far during the coronavirus pandemic? https://www.healthsystemtracker.org/chart-collection/how-have-healthcare-utilization-and-spending-changed-so-far-during-the-coronavirus-pandemic/#item-start

Prominent Australian and Russian Research Institutions Join Global Virus Network to Combat Viral Diseases

Center for Emerging Viruses, Inflammation and Therapeutics of the Menzies Health Institute Queensland (MHIQ) at Griffith University, Australia and the Chumakov Federal Scientific Center for Research and Development of Immune and Biological Products of the Russian Academy of Sciences Join GVN at Critical Time for Information Sharing

Baltimore, Maryland, USA, September 8, 2020: The Global Virus Network (GVN), comprising foremost experts around the world in every class of virus-causing disease in humans and some animals, , today announced the addition of the Center for Emerging Viruses, Inflammation and Therapeutics (EVIT) of the Menzies Health Institute Queensland at Griffith University, Australia and the Chumakov Federal Scientific Center for Research and Development of Immune and Biological Products of the Russian Academy of Sciences as its newest Centers of Excellence. The two new institutions bring GVN’s total number of Centers of Excellence to 57, along with 10 affiliates in 33 countries.

“We are pleased to have these premier institutions join us from Australia and Russia at this critical time in the global pandemic,” said Christian Bréchot, MD, PhD, who is President of the GVN and Professor at the University of South Florida.  “EVIT will strengthen our depth and collaborative network in arbovirology, particularly in the Asia-Pacific region, Southeast Asia, India, South America and South Africa. The Chumakov Center has unique expertise in varying areas of virology with many global connections, making it Russia’s leading research organization in the field of virology.”

EVIT, as part of the Menzies Health Institute Queensland, provides a critical mass of scientists and clinicians with distinct areas of expertise in emerging arbovirus diseases. The Center has excellent knowledge of viral pathogenesis and related inflammatory diseases and strong capabilities in developing treatments for emerging viruses such as chikungunya (CHIKV), Ross River (RRV), dengue, Zika (ZIKV), Japanese encephalitis (JEV) and West Nile (WNV) viruses.  Additionally, EVIT focuses on emerging viruses such as Hendra and SARS-CoV-2, and established viruses such as influenza virus and respiratory syncytial virus. The Center has a strong emphasis on both basic and translational research, which has led to several major breakthroughs in understanding how viruses cause disease. The GVN Center is led by Suresh Mahalingam, PhD, FASM, FAAM, Professor and Director, Emerging Viruses, Inflammation and Therapeutics Group, Principal Research Leader and NHMRC Senior Research Fellow at EVIT.

“GVN has the ability to contribute to the activities of major players in world health such as CEPI and GAVI, which will open up additional opportunities for our research center to establish new collaborations,” said Dr. Mahalingam. “Further, through our GVN membership, we look forward to enhancing our leadership of arbovirus research and disease preparedness in the Asia-Pacific region; establishing new collaborations with fellow GVN members; facilitating advanced training of students and researchers from the Asia-Pacific region; and, enhancing technology and knowledge transfer within the GVN.”

The Chumakov Center conducts a broad range of studies of different human and animal viruses and manufactures polio, rabies and tick-borne encephalitis vaccines, supplying up to 70% of national demand in these products. Yellow fever vaccines produced at the Chumakov Center cover more than a half of UNICEF’s Eliminating Yellow Fever Epidemics (EYE) Strategy, supporting immunization in more than 50 countries.  The Chumakov Center contains the World Health Organization’s (WHO) regional reference laboratory for polio preforming epidemiological surveillance of acute flaccid paralysis and polio as a part of Global Polio Laboratory Network for Global Polio Eradication Initiative. The Center also acts as a WHO Collaborative Center for Poliomyelitis and Enterovirus Surveillance and Research. The Center is led by Aydar Ishmukhametov, MD, DSc, Director General of the Chumakov Center and a member of the Russian Academy of Sciences.

“Our expertise in research, preclinical and clinical development and manufacturing of antiviral vaccines will be useful for GVN members.,” said Dr. Ishmukhametov.  “We look forward to collaborating with the world’s leading virology experts and for participation of our younger scientists in virology training programs through the GVN.”

About the Global Virus Network (GVN)

The Global Virus Network (GVN) is essential and critical in the preparedness, defense and first research response to emerging, exiting and unidentified viruses that pose a clear and present threat to public health, working in close coordination with established national and international institutions. It is a coalition comprised of eminent human and animal virologists from 57 Centers of Excellence and 10 Affiliates in 33 countries worldwide, working collaboratively to train the next generation, advance knowledge about how to identify and diagnose pandemic viruses, mitigate and control how such viruses spread and make us sick, as well as develop drugs, vaccines and treatments to combat them. No single institution in the world has expertise in all viral areas other than the GVN, which brings together the finest medical virologists to leverage their individual expertise and coalesce global teams of specialists on the scientific challenges, issues and problems posed by pandemic viruses. The GVN is a non-profit 501(c)(3) organization. For more information, please visit www.gvn.org. Follow us on Twitter @GlobalVirusNews.

Media Contact:

Nora Samaranayake, GVN
410-706-1966
nsamaranayake@gvn.org

Will Neutralizing and Therapeutic Antibodies Play a Role in the Treatment of COVID-19?

Interest has increasingly been focused on the potential of virus-neutralizing monoclonal antibodies (mAbs) to treat COVID-19 by passive immunization. These antibodies generally target the viral spike protein to prevent infection by blocking ACE2 receptor binding to its receptor binding domain (RBD). There are several issues, however, that need to be addressed to determine when and how they might be used. First, the levels of neutralizing antibodies present in COVID-19 patients do not always correlate to the severity of the disease, and the mean time for seroconversion in SARS patients is known to be about 2 weeks after disease onset. It is possible that timing is critical; i.e., perhaps lack of such antibodies early in infection allow vigorous viral replication, and high levels of antibody production after the development of symptom can be too late to do much good. It may be that the T cell response also plays an important role in the course of infection. Second, although immune serum from recovered patients has been touted as a potential therapy with some successful cases, evidence of its effectiveness is at best contradictory (1).

Another consideration is the nature of the antibodies themselves. This is challenging because protective immunity against SARS-CoV-2 remains unknown. Specifically, the levels and types of antibodies required for the protection need to be defined. Neutralizing antibodies against SARS-CoV-2 appear to have two sets of targets. Some bind the RBD, while others bind the spike protein outside the RBD. Some antibodies bind to the spike protein but do not neutralize the virus (non-neutralizing antibodies). Yet another consideration is that some neutralizing antibodies can lead to antibody-dependent enhancement (we have covered this in an earlier GVN Perspectives) when they are at sub-optimal concentrations. It is obvious that great care must be taken in selecting mAbs for therapeutic development. It also seems intuitive that a mixture of mAbs targeting different epitopes would provide an extra measure of protection. In clinical use, successful treatment will depend critically upon the time of mAbs administration, doses, levels of concentrations, and duration of treatment.

The general approach to identify effective antibodies has been to identify infected patients with high titers of neutralizing antibodies, sort and recover their memory B cells, sequence the heavy and light chain of mRNAs from single sorted cells to characterize the antibody produced by each cell, synthesize their mRNAs with codon optimization for high levels of expression, clone them into expression vectors and express them in transfected cells, and then screen the resultant antibody library. This has become a standardized approach to generate recombinant neutralizing antibodies (2-8). In general, they fall into two categories. The primary group of antibodies, as might be expected, targets the receptor binding domain (RBD) of the spike protein, presumably blocking its binding to the ACE2 receptor. Others bind the N-terminal domain (NTB) of the spike protein. It is not clear how these NTB antibodies neutralize SARS-CoV-2. Presumably, this is by causing allosteric changes in the tertiary or quarternary structure of the spike trimer. Currently identified neutralizing antibodies against SARS-CoV-2 are closely related to germline sequences and do not show signs of hypermutation. This indicates that neutralizing antibodies have been derived with relatively few changes from germline sequences and is a favorable sign for successful vaccine development. It would likely be best for mAb therapeutic use to include antibodies targeting both the RBD and the NTD domains of the spike protein. It should be pointed out that most neutralization assays were done with Vero (monkey kidney) cells, which are not infected by the same pathway as human airway cells(9), although ACE2 binding is required for both pathways.

Importantly, administration of neutralizing mAbs have proven to be protective in several animal models of COVID-19, including rhesus macaques, hamsters, and mice expressing human ACE2(3, 6, 8, 10-12). It is important to note that the mAbs were administered prior to or shortly after challenge. Thus, the results apply to prophylactic or early therapeutic use, but not necessarily to general therapeutic use.

As with other antivirals, it will likely be critical to administer mAbs early in disease, or as a prophylactic. Many patients with serious disease already have high levels of neutralizing antibodies, but these do not appear to ameliorate disease severity, presumably because dysregulated immune responses are driving pathogenesis in these settings. It will also be important to determine what constitutes an effective dose as well as the biologic half-life of any protective effect.

We should mention some recently described “dark horses” for prophylactic passive immunization. These are engineered single chain single domain antibody-like proteins, called nanobodies, that are derived from camelid species (llamas, alpacas). Camelids make normal antibodies, but they also make antibodies comprised of a single heavy chain containing constant and hinge domains linked to a variable region capable of binding antigens. Interestingly, the variable domain alone is also capable of binding antigens. The variable domain is about 1/10th the size of normal antibodies; hence the name nanobody. Because of this, they are far more stable than normal antibodies, allowing them to be lyophilized, heated, and aerosolized. Their small size makes them able to penetrate tissue more readily than do normal antibodies. And they are easy to produce, which makes them scalable.

Nanobodies that are able to bind the SARS-CoV-2 spike protein (both within the RBD and outside the RBD) were identified from a yeast library of synthetic nanobody sequences. Their tiny size allowed them to be trimerized with gly-ser linkers, thus yielding a multivalent molecule with greatly increased potency.  They were then subjected to saturation mutagenesis and affinity maturation, yielding at least one nanobody with picomolar neutralization potency and sub-picomolar affinity. Similar nanobodies have been isolated from a llama immunized with stabilized SARS-CoV-2 spike protein(13). Potency was increased by creating a bivalent molecule with two linked nanobodies.

Because of their size and stability, nanobodies are easily produced and stable to aerosolization. This should make it feasible to package them in inhalers. Introduction to airway tissue would be direct to potential sites of infection. They might, thus, serve as an effective prophylactic, since it would be simple to self-administer them daily. If so, they could be a game changer, but as with other potential therapeutic possibilities, the proof will be in the results.

More than 70 antibody therapies are being developed for the treatment of COVID-19. There has been anticipation that monoclonal antibodies may provide short-term protection from SARS-CoV-2 and could serve as important components of the COVID-19 pandemic response until vaccines become available. Two Phase 3 clinical trials are currently underway in the US. In general, mass-produced antibodies are complex to manufacture and are expensive. Therefore, their availability in low- and middle-income countries can be very limited. It will be also important to have a breakthrough to produce cost-effective, large quantities of antibodies.

 

 

  1. L. Li et al., Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA, (2020).
  2. P. J. M. Brouwer et al., Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability. Science 369, 643-650 (2020).
  3. Y. Cao et al., Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients’ B Cells. Cell 182, 73-84 e16 (2020).
  4. X. Chi et al., A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. Science 369, 650-655 (2020).
  5. B. Ju et al., Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature 584, 115-119 (2020).
  6. L. Liu et al., Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature 584, 450-456 (2020).
  7. Y. Wu et al., A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2. Science 368, 1274-1278 (2020).
  8. S. J. Zost et al., Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature 584, 443-449 (2020).
  9. M. Hoffmann et al., Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2. Nature, (2020).
  10. A. O. Hassan et al., A SARS-CoV-2 Infection Model in Mice Demonstrates Protection by Neutralizing Antibodies. Cell 182, 744-753 e744 (2020).
  11. J. Kreye et al., A SARS-CoV-2 neutralizing antibody protects from lung pathology in a COVID-19 hamster model. bioRxiv, (2020).
  12. R. Shi et al., A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature 584, 120-124 (2020).
  13. D. Wrapp et al., Structural Basis for Potent Neutralization of Betacoronaviruses by Single-Domain Camelid Antibodies. Cell 181, 1004-1015 e1015 (2020).

Global Virus Network’s Institute of Human Virology and Italian Researchers identify a SARS-CoV-2 Viral Strain with Deletion in a Protein, Possibly Reducing Fatalities

A deletion in a protein, NSP1, which is important for reducing innate immune response may signal emergence of a less pathogenic viral strain

Baltimore, Maryland, USA, August 24, 2020: The Institute of Human Virology (IHV) at the University of Maryland School of Medicine, a Global Virus Network (GVN) Center of Excellence, in collaboration with scientists from Campus Biomedico in Rome, Italy announced today the results of studies showing the emergence of a SARS-CoV-2 viral strain with a deletion in a protein known as nsp1.  These data, accepted for publication today by the Journal of Translational Medicine, may indicate the emergence of a less pathogenic viral strain.

“Nsp1 plays a central role in hampering the anti-viral innate immune response,” said Robert C. Gallo, MD, The Homer & Martha Gudelsky Distinguished Professor, Co-founder & Director at the Institute of Human Virology, University of Maryland School of Medicine and Co-Founder and Chairman of the International Scientific Leadership Board of the Global Virus Network (GVN).  “Our data indicate that a small percentage of SARS-CoV-2 viruses is harboring a deletion in an important protein responsible for hampering the innate immune response, possibly adapting toward a decrease in pathogenicity. Scientists, including those within the Global Virus Network, will be able to expand on these data to confirm how widespread this deletion is.”

The researchers analyzed SARS-CoV-2 genome sequences from several countries and discovered a previously unknown deletion that is widespread and spans varying geographical areas. Modelling analysis of the newly identified deletion of SARS-CoV-2 nsp1 suggests that this deletion could affect the structure of the C-terminal region of the protein, important for both regulating viral replication and hampering the innate immune system response. The research indicates that the virus may become less pathogenic.

“SARS-CoV-2 seems to be undergoing profound genomic changes, but the effect of such changes on viral pathogenesis may become visible over a long period of time”, said Davide Zella, PhD, Assistant Professor of Biochemistry and Molecular Biology at the Institute of Human Virology, University of Maryland School of Medicine and member of the Global Virus Network (GVN).  “We need to confirm the spreading of this particular viral strain and research potential strains with other deletions in the nsp1 protein, both in the population of asymptomatic and pauci-symptomatic subjects, and correlate these changes in nsp1 with decreased viral pathogenicity. Also, the spreading of this deletion needs to be evaluated over time”.

“The percentage of deletions found in the cases analyzed did not seem to be geographically homogenous, possibly due to the low number of available sequences for analysis,” said Francesca Benedetti, PhD, Research Associate of Biochemistry and Molecular Biology at the Institute of Human Virology, University of Maryland School of. Medicine “The percentage was higher in Sweden with 1.89% while in certain parts of the United States was about 1%.”

“Our modeling of nsp1 protein of SARS-CoV-2 indicates that this deletion may influence potential structure in this region, thereby altering its activity and ability to interact with other proteins of the host,” says Greg Snyder, PhD, Assistant Professor of Microbiology and Immunology at the Institute of Human Virology, University of Maryland School of Medicine.

“We are pleased to work with our colleagues at the Institute of Human Virology to identify and characterize the profound alterations in the SARS-CoV-2 genomic sequences spanning the globe, and to evaluate their biological significance,” said Massimo Ciccozzi, PhD, Associate Professor of Medical Statistics, Universita’ Campus Biomedico in Rome, Italy.

# # #

About the Institute of Human Virology

Formed in 1996 as a partnership between the State of Maryland, the City of Baltimore, the University System of Maryland, and the University of Maryland Medical System, the IHV is an institute of the University of Maryland School of Medicine and is home to some of the most globally-recognized and world-renowned experts in all of virology. The IHV combines the disciplines of basic research, epidemiology, and clinical research in a concerted effort to speed the discovery of diagnostics and therapeutics for a wide variety of chronic and deadly viral and immune disorders – most notably, HIV the virus that causes AIDS. For more information, visit www.ihv.org and follow us on Twitter @IHVmaryland.

 

About the Global Virus Network (GVN)

The Global Virus Network (GVN) is essential and critical in the preparedness, defense and first research response to emerging, exiting and unidentified viruses that pose a clear and present threat to public health, working in close coordination with established national and international institutions. It is a coalition comprised of eminent human and animal virologists from 55 Centers of Excellence and 10 Affiliates in 33 countries worldwide, working collaboratively to train the next generation, advance knowledge about how to identify and diagnose pandemic viruses, mitigate and control how such viruses spread and make us sick, as well as develop drugs, vaccines and treatments to combat them. No single institution in the world has expertise in all viral areas other than the GVN, which brings together the finest medical virologists to leverage their individual expertise and coalesce global teams of specialists on the scientific challenges, issues and problems posed by pandemic viruses. The GVN is a non-profit 501(c)(3) organization. For more information, please visit www.gvn.org. Follow us on Twitter @GlobalVirusNews

 

GVN MEDIA CONTACT
Nora Samaranayake
Phone:  410-706-1966
Email:    nsamaranayake@gvn.org

 

From molecular biology to human retroviruses: in memory of GVN Italy Center Director Umberto Bertazzoni (1937-2020)

Born in Trissino (VI) in 1937, Umberto Bertazzoni graduated from the University of Pavia in Pharmacy (1960) and in Biological Sciences (1964). He was a researcher at the Joint Research Center of Ispra from 1964 to 1974, researcher at the Institute of Genetics of the CNR of Pavia from 1974 to 1994 and Head of Unit at the Directorate General for Research of the European Commission in Brussels from 1995 to 2000. He also carried out research activity in 1962 at the University of Iowa, USA; from 1971 to 1974 at the J. Monod Institute of the University of Paris VII; in 1979 and 1992 at the Naval Hospital and the NIH in Bethesda, USA. He was full professor of Molecular Biology at the University of Verona from 1990 to 2010 in the degree course of Medicine and Surgery. Prof. Bertazzoni was a Center of Excellence Director of the Global Virus Network (GVN) Italy. He authored of 110 indexed publications (h-index: 28; source. Scopus).

Prof. Umberto Bertazzoni received the “Giovanna Tosi” Prize for Cancer Research at the University of Insubria in September 2018 “For his seminal studies on human oncogenic retroviruses and for his tireless activity in foundation and support of international virology Institutions” which perfectly summarizes his long scientific life, recalls Luigi “Gino” Chieco-Bianchi (University of Padua), perhaps his closest friend, as well as collaborator and first Director of GVN Italy.

Umberto Bertazzoni in Red Square, Beijing, China during GVN’s 2015 International Meeting

Prof. Chieco-Bianchi continued, “I met Umberto in the early 1980s when, an established researcher at ISPRA (Higher Institute for Environmental Protection and Research), he dealt with the molecular mechanisms underlying the proliferation of neoplastic cells [his works on Tdt, terminal deoxynucleotidyl transferase , are among the most cited of that period – (1, 2)]. With the advent of AIDS, his skills in enzymology became invaluable for the study of reverse transcriptase, the key enzyme of retroviruses such as HIV (human immunodeficiency virus, cause of AIDS) and HTLV (human T lymphotropic virus, the first pathogenic human retrovirus, discovered in 1980, and causative agent of a relatively rare form of adult T-cell leukemia and neurological syndromes). Umberto immediately became part of the group of “human retrovirologists”, initially not very numerous – which I too had joined in after abandoning my studies on murine retroviruses – soon conquering a leading position in the study of HTLV. Those were years of intense and enthusiastic work: many young scholars, who returned from the USA and various European countries, where they had acquired new skills, were recruited together with the most valid Italian research groups in the National AIDS Project, adequately funded by the Ministry of Health and managed by the Istituto Superiore di Sanità under the intelligent and rigorous scientific direction of Giovanni Battista Rossi. Umberto participated assiduously in the periodic meetings, very animated, in which the various Operational Units of the Project reported the results achieved, thanks to which Italy in those years established itself among the leading countries for AIDS research.”

In the mid-1990s he took on an important position at the EU Research Directorate General where he was also head of the Infectious Diseases section, coordinating among other things the European projects on AIDS. The main focus of his research was the study of the characteristics of HTLV-2 (a substantially non-pathogenic virus for humans) and of its molecular and functional differences compared to HTLV-1 (absent in Italy) with the intent to clarify the absence of oncogenicity observed in infected individuals, in general drug addicts or former drug addicts. The results of these studies have been the subject of relevant publications, as evidenced by having been editor (with Vincenzo Ciminale of the University of Padua and Maria Grazia Romanelli, his close collaborator at the University of Verona) of a monographic issue of Frontiers of Microbiology dedicated to HTLV-1 (3).

Luigi “Gino” Chieco-Bianchi and and Umberto Bertazzoni

Prof. Chieco-Bianchi said, “With Umberto I also shared the adventure of the Global Virus Network (GVN), founded in Washington in 2011 by Bob Gallo of the U.S., Billy Hall of Ireland and the late Reinhardt Kurth of Germany. Bob wanted me to initially be the coordinator of the Italian Center of Excellence and so, with Umberto, Roberto Accolla, Franco and Luigi Buonaguro, Beppe Ippolito and Guido Poli, all armed with goodwill but lacking operational resources, we began to set up that involved old and young Italian virologists. After three years, due to physiological turnover, Umberto was unanimously designated to lead GVN Italy and for another three years, more effectively, he carried out his coordinating role, always animated by enthusiasm and confidence in the future.

Prof. Robert Gallo (Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA, Global Virus Network): “Umberto Bertazzoni was a scientific close colleague and personal friend for four decades. I always enjoyed his company and his wonderful enthusiasm for our similar scientific interests. He was early in HTLV research and some of its pioneering studies.  He was a leader in the early formation of the GVN and instrumental in its activities. He will be missed very much, but always remembered.”

Prof. Guido Poli (Vita-Salute San Raffaele University, Milan, Global Virus Network): “Immediately after his return to the University of Verona, a relationship of collaboration and friendship emerged largely mediated by his collaborator Claudio Casoli who also left us a few months ago. The intersection of our scientific interests was based on HIV-1 and HTLV-2 co-infection, mainly in drug addicts or ex-drug addicts. Keen to our scientific collaboration was the discovery in 1995-1996 of the fundamental role of CCR5-binding chemokines (and to a lesser extent CXCR4), a key receptor for HIV-1 entry into target cells. Not surprisingly, the study by Paolo Lusso and Robert Gallo of December 1995 (4) exploited the production of these chemokines by T lymphocytes immortalized by HTLV-1 or HTLV-2. We then demonstrated together with Umberto, Claudio and their collaborators that patients co-infected with HTLV-2 and HIV-1 often had the characteristics of Long-Term Non-Progressors, that is, they demonstrated a natural predisposition to control the progression of HIV-1 disease, thanks to the hyperproduction of a particularly powerful chemokine (5). Beyond his objective scientific merits, with Umberto Bertazzoni disappears one of the last ‘gentlemen scientists’ around.”

Umberto Bertazzoni and Guido Poli in Red Square, Beijing, China during GVN’s 2015 International Meeting

Prof. Davide Zella (Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA, Global Virus Network): “I met Umberto in 1984, at the CNR in Pavia, as a young university student. Life in his laboratory was very pleasant: I was learning and having fun. I remember the time spent discussing science, and he would have guided me towards the thesis. At the beginning he was ‘the professor,’ but he quickly became ‘Umberto,’ a friend who over time would have given me advice, at times assuming the appearance of a father figure. With the arrival of AIDS, Umberto introduced me to Robert Gallo in Florence in 1992 and from there my career began with Gallo, with whom I still work today. Umberto taught me a lot, in the laboratory and in life, and I will miss him very much.”

Franco M. Buonaguro (“Center Director”), Roberto Accolla, Luigi Buonaguro, Gino Chieco-Bianchi, Giuseppe Ippolito & Guido Poli for GVN-Italy.

 

References

  1. Bertazzoni U, Stefanini M, Noy GP, Giulotto E, Nuzzo F, Falaschi A et al. Variations of DNA polymerase-alpha and -beta during prolonged stimulation of human lymphocytes. Proc Natl Acad Sci U S A. 1976; 73 (3): 785-9
  2. Bertazzoni U, Brusamolino E, Isernia P, Scovassi AI, Torsello S, Lazzarino M et al. Prognostic significance of terminal transferase and adenosine deaminase in acute and chronic myeloid leukemia. Blood. 1982; 60 (3): 685-92
  3. Bertazzoni U, Ciminale V, Romanelli MG. Editorial: Molecular Pathology of HTLV-1. Front Microbiol. 2018; 9: 3069
  4. Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8 + T cells. Science. 1995; 270 (5243): 1811-5
  5. Pilotti E, Elviri L, Vicenzi E, Bertazzoni U, Re MC, Allibardi S et al. Postgenomic up-regulation of CCL3L1 expression in HTLV-2-infected persons curtails HIV-1 replication. Blood. 2007; 109 (5): 1850-6

Hydroxychloroquine-What’s the Deal?

The absence of efficient therapeutics for COVID-19 has brought much attention to evaluation of repurposing drugs. Hydroxychloroquine (HC) is an antimalarial drug that affects endosomal function and blocks autophagosome-lysosome fusion (1). Since coronaviruses use the endolysosomal pathway to enter the cell before uncoating, HC has been shown to inhibit SARS-CoV-2 replication in cellular models. The use of HC in the treatment and/or prevention of COVID-19 has been clouded in controversy and contention. Partly, this is because it has become somewhat of a political football, with one side relentlessly touting its value and with the other side just as adamantly claiming that it has no value and is indeed harmful with various side effects. The second reason is the variety of conditions used in the reported tests. The third reason is that there seems to be a great number of risk factors or co-morbidities, and this can result in vastly different results due to differences in demographics. Results from anecdotal versus retrospective versus observational versus controlled versus randomized/blind trials have varied widely. There is also the question of whether it is necessary to include azithromycin (AZM) or other antibiotics, and whether to use zinc (Zn).  AZM, a widely used broad-spectrum antibiotic, also blocks autophagosome clearance in human cells and replication of the Zika and influenza viruses in human cells in vitro. A subset of HC advocates also thinks that inclusion of zinc is critical, and that the primary function of HC is to help Zn enter the cells.  The related drug, chloroquine, has been reported to act as a Zn ionophore(2), and Zn inhibits RNA chain elongation by SARS-CoV-1 RNA-dependent RNA polymerase in vitro(3). The authors also showed inhibition of viral infection in Vero (African green monkey kidney) cells. However, it has recently been shown that SARS-CoV-2 enters Vero cells by an alternate pathway that is not inhibited by HC. Due to the use of a different pathway for viral entry,  HC treatment in human lung cells did not significantly inhibit viral infection (4). These data suggest that if HC has a beneficial effect on treatment of COVID-19, it is either because it affects the host response to the virus or it affects a step unrelated to viral entry.

For all these reasons, studies that include randomized control groups are inherently far more reliable than observational or retrospective studies, in which data from other groups are used as a control. Thus, without randomized trials, it is difficult to draw firm conclusions. Double-blind randomized studies are the most reliable because they eliminate potential placebo effects, which can be substantial. Randomized trials are, however, more expensive and take more time to carry out, so there are far fewer of them than of observational or retrospective studies.  Sorting out all these issues is difficult, but let’s give it a try. The sources we will consider will include PubMed (comprised of peer-reviewed published studies), medRvix (preprints not yet peer-reviewed), and the internet in general (with the uncertainty that entails), including press releases and editorials, perhaps the least reliable source. We will not consider in vitro antiviral studies, as these have been performed largely with Vero cells, which as discussed above, are not useful for SARS-CoV-2 studies and HC.

Reviewing the Literature

Let’s first consider results from several randomized double-blind trials with HC. One such study looked at people with documented occupational or household exposure to individuals with confirmed COVID-19 to observe whether HC was effective prophylactically(5). Treatment with HC was for 5 days within 4 days of exposure, and both groups had somewhat more than 400 subjects. There were slightly but insignificantly fewer cases of COVID-19 in the HC arm, as judged by either a positive PCR test or development of symptoms. There was one hospitalization in each group, and no deaths occurred. HC was not associated with any serious side effects. Another randomized double-blind trial looked at patients with early COVID-19(6). Subjects were treated with HC or placebo for 5 days. There was no difference in symptom severity over 14 days between the groups. There were 4 hospitalizations and one death in the HC group compared to 8 hospitalizations and one death in the placebo group; this did not reach statistical significance. Another small randomized double blind study compared two groups (n=40) of COVID-19 patients treated with either high or lower doses of chloroquine for 10 days(7). All were taking AZM. Although there was more mortality in the high dose group, neither differed significantly from what would be expected from an untreated group of similar patients. We note that not having an internal untreated control weakens this study. Taken together, these trials strongly suggest that there is not a significant therapeutic benefit of HC, although they do not completely rule it out. In fact, the authors in these studies generally do not prove a lack of potential benefit of HC, but suggest further similar studies are needed for confirmation. The data also uniformly suggest that HC is reasonably safe.

There have also been several well controlled large randomized open-label (not blinded) trials. Among these was one testing hospital patients with COVID-19 and requiring either no supplemental O2 or <4 l/min O2. More than 500 patients were randomly assigned to 3 groups and treated for 7 days by standard of care (SOC), HC+SOC, and HC+AZM+SOC(8). Clinical status was evaluated at 15 days. There was no improvement in either group receiving HC relative to the SOC group. Elevated Q-T heart intervals and elevated liver enzymes were more prevalent in these two groups, but these were not considered serious. Another randomized open label study looked at patients with mild to moderate COVID-19 and treated them either with SOC (n=75) or SOC+HC (n=75)(9). As judged by conversion to negativity for SARS-CoV-2, judged by RT-PCR of nasal swabs, and by alleviation of symptoms, there were no differences in outcomes by day 28. Some negative events were attributed to HC, primarily diarrhea. Another randomized open label trial researched 293 patients with COVID-19 who were not hospitalized and were symptomatic for fewer than 5 days. Patients were treated either with HC for one week (n=136) or without HC (n=157). As judged by viral RNA loads, hospitalization and time to resolution of symptoms, there were no significant differences.  We note that the number of hospitalizations was too small to reach significance. Yet another randomized non-blind trial looked at patients with mild COVID-19. Patients were treated with HC for 6 days or not treated and viral RNA loads, and resolution of symptoms at day=28 were the end points. There were about 140 in each arm. No differences in outcomes were noted, and no adverse effects were reported. In contrast, another small randomized study treated patients with HC (including pneumonia) for 5 days (no AZM or Zn) or SOC (31 subjects per group) and showed a significant improvement in cough and fever resolution. The reasons for the incongruent results are unclear.

Next in degree of reliability are observational or retrospective studies, as they generally rely on statistics from patient groups that are distinct from the groups under study and may differ by genetic factors or by comorbidities. They may also differ by prior exposure to other coronaviruses or by prevalence of recent or childhood administration of vaccines such as BCG, polio or measles, all of which may affect results from SARS-CoV-2 exposure or infection because of immune memory and cross-reactivity. In general, more observational studies report a protective effect than do those that find no benefit of HC.  The quality of these studies varies widely. As with randomized studies, in general, the larger the study, the more likely the results are to be accurate. We will concentrate on several of the best and largest of these; they are reasonably representative of the multitude of observational studies.

A large (~3,700 patients) retrospective/observational study reported a benefit of HC plus AZM treatment for 5 days (n=3,119) compared to groups treated with HC alone, AZM alone or SOC (n=619), termed “others.”  Better outcomes compared to “others” were reported for mortality, hospitalization, duration of viral RNA shedding, and several other clinical parameters. It is not clear, however, as to how patients were assigned to treatment groups, and patients not receiving HC seemed sicker, judged by prevalence of cancer or hypertension. It should also be noted that there was no report of Zn usage.  A large multi-center (~2,500 patients) study treated patients with HC alone, AZM alone, HC+AZM, or neither(10) and looked at mortality rates as the primary outcome. Taking into accounts various clinical parameters from each group, the authors concluded that HC provided a hazard ratio reduction of 66% and HC+AZM a reduction of 71%. This may not account for all possible confounding factors. For example, it is not clear why the untreated patients were not given HC or whether they were sicker at admission. However, the patients not receiving HC were on average 5 years older and had a higher incidence of cancers, which seem to be serious confounding factors. It is also not totally clear how the decision was made to not administer HC. It should also be noted that steroids were administered to patients receiving HC as adjunct therapy at a far greater rate than those who did not; this is another potential substantial confounding effect. Duration of symptoms before admission were not available. Indeed, the authors caution that randomized prospective trials are needed and that their results should be interpreted with caution. There were no reported major safety issues. Again, we note there was no reported use of Zn.

Another observational study supporting a positive effect of HC looked at ~1,600 patients who were treated with one of 16 different treatments, with death or intubation as an endpoint. The only favorable treatments were HC (with a hazard ratio of 0.83) and predisone (HR=0.85). Dexamethasone treatment resulted in slightly worse outcomes. The same caveats mentioned for the previous studies are applicable to this study.

Another retrospective study with 335 subjects were apparently drawn from subjects treated by Dr. V Zelenko, who at one point claimed to have treated 1500 people with COVID-19 successfully, although this was based on symptoms rather than confirmed tests. It seems likely, based on the size of the cohort tested (335), that not all of the original patients were positive.  (For comments on this point, please read here). 141 patients were treated with HC+AZM+Zn. Oddly, public reference data on 377 patients from the same community were used as a control rather than patients in the cohort who were untreated, and no clinical or demographic data are available for this group. Although there were significantly fewer hospitalizations and deaths and no serious adverse effects in the treated group, the authors state that no conclusions can be made on efficacy or safety. This study appears to be where the idea that Zn was critical originated.

There are also observational/retrospective studies that show no effect or HC±AZM. One looked at 226 patients with mild to moderate COVID-19 who were either treated or received SOC.  No benefit was observed as judged by viral clearance, hospital stay, or duration of symptoms. It should be pointed out the treated group was relatively small (N=31). Salvarani et al. (11) looked at 4,400 people who were being treated with antimalarial drugs (HC or chloroquine) and compared them with the general population in the same geographic areas. There were no significant differences in rates of diagnoses of COVID-19 nor of positive tests for SARS-CoV-2. Geleris et al. (12) studied 1376 hospitalized COVID-19 patients, of whom 811 were treated within 48 hrs with a 5 day course of HC; the remainder were given SOC. There was no significant difference in intubation or death. As with non-randomized studies, differences in characteristics of cohorts can matter greatly. The HC-treated cohort, for example, was older and had more hypertension than the reference cohort. The Geleris study did use propensity score matching to account for these differences. The authors, however, caution that randomized trials are needed to conclude HC has no value for COVID-19.

There are many more studies than we have described, and it would not be feasible to mention them all. We have, however, tried to be as representative as possible. As we can see, there are considerable differences in outcomes reported. Looking at the data in general, it can be seen that the randomized trials have the most agreement, and most (but not all) conclude that there is no significant benefit to HC treatment with or without AZM. Concerning the observational/retrospective studies, there are more positive than negative reports. Why is this? As discussed, these are inherently less reliable than randomized trials. It may thus be easier to get positive results in an observational trial, especially if the study is small or not well controlled by cohort. Also, it is likely that positive studies in general (not simply COVID-19 and HC) are more readily publishable than negative ones. Although Zn is claimed to be critical, it should be noted that many of the positive reports do not use Zn, which would seem to negate this idea. The placebo effect may play a role.

Conclusion

Our literature review has generated somewhat contradictory findings, but strongly suggests that HC is not beneficial for COVID-19 treatment. There are positive data as well, but these come almost entirely from observational/retrospective studies, with their attendant uncertainties. However, it cannot be excluded that HC is of great benefit to an as of yet uncharacterized subset of patients. As to safety issues, there appears to be general agreement that side effects are relatively minor, and HC does not appear to be very dangerous, as would be expected from long experience with HC in connection to malaria and rheumatoid arthritis. There is far more heat than light in the public discourse on HC (internet, editorials, press releases, etc.) It will be difficult to prove benefit or safety to those whose political views inform their judgements, but we believe we have provided a balanced analysis. In addition, the U.S. Food and Drug Administration (FDA) cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems (13). We realize many of the studies represent something akin to battlefield medicine, are meant to save lives, and should generally be applauded, but until more blinded randomized trials are reported, it is difficult for us to ascribe value or harm to HC.

 

 

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