The story behind COVID-19 vaccines
PHOTO: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Amid the staggering amount of suffering and death during this historic pandemic of COVID-19, a remarkable success story stands out. The development of several highly efficacious vaccines against a previously unknown viral pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in less than 1 year from the identification of the virus is unprecedented in the history of vaccinology. A frequently asked question is how such an extraordinary accomplishment could have been realized in such a short time frame, when timelines for other vaccines are measured in years if not decades. In fact, concern about this truncated timeline has contributed in part to the hesitancy in accepting these vaccines. What is not fully appreciated is that the starting point of the timeline for SARS-CoV-2 vaccines was not 10 January 2020, when the Chinese published the genetic sequence of the virus. Rather, it began decades earlier, out of the spotlight.
Two activities predate the successful COVID-19 vaccines: the utilization of highly adaptable vaccine platforms such as RNA (among others) and the adaptation of structural biology tools to design agents (immunogens) that powerfully stimulate the immune system. The RNA approach evolved over several years owing to the ingenuity of individual scientists, including Drew Weissman and Katalin Karikó, and the concentrated efforts of several biotech and pharmaceutical companies.
The discovery of an immunogen adaptable to the multiple platforms (messenger RNA and others) used for COVID-19 vaccines resulted from collaboration across different scientific subspecialities. At the Vaccine Research Center (VRC) of the U.S. National Institute of Allergy and Infectious Diseases, a group led by Peter Kwong had for several years used tools of structure-based vaccine design to determine the optimal structural conformation of a trimeric protein on the surface of the virus (the envelope protein) that allows HIV to bind to cells and ultimately trigger the production of antibodies that neutralize many HIV viral strains. Although this sophisticated approach has not yet led to a successful HIV vaccine, it caught the attention of another VRC investigator, Barney Graham, who was interested in generating a vaccine for respiratory syncytial virus (RSV). Graham joined Jason McLellan (of Kwong's team) to adapt a structure-based approach to an RSV vaccine. They identified the prefusion conformation of the viral spike protein as highly immunogenic and created mutations to stabilize that conformation for successful use as an immunogen. This was a huge step toward the creation of a successful RSV vaccine.
VRC researchers and colleagues then built on the RSV advances. Graham's team, including Kizzmekia Corbett, and collaborators in the laboratories of McLellan and Andrew Ward adopted this approach of mutational stabilization of prefusion proteins in their work on the spike protein of the coronaviruses that cause Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). So, when the genetic sequence of the SARS-CoV-2 became available, Graham's team lost no time in joining their long-time collaborators at Moderna to develop an RNA vaccine using a stabilized, prefusion spike protein as the immunogen. Pfizer and BioNTech, where Karikó was working, also used the RNA platform that she and Weissman had perfected and the immunogen designed by Graham to develop an RNA vaccine. Additional companies also used Graham's immunogen in other vaccine platforms that had been evolving for years, to make SARS-CoV-2 vaccines.
SARS-CoV-2 vaccines based on the new immunogen rapidly moved to clinical trials. Several of these vaccines were tested in phase 3 efficacy trials at a time when the level of community spread of SARS-CoV-2 was extremely high, allowing vaccine efficacy endpoints of greater than 90% to be reached in a timely fashion. The speed and efficiency with which these highly efficacious vaccines were developed and their potential for saving millions of lives are due to an extraordinary multidisciplinary effort involving basic, preclinical, and clinical science that had been under way—out of the spotlight—for decades before the unfolding of the COVID-19 pandemic. When the stories and recounting of this pandemic are written, it is important that this history not be forgotten, as we are reminded once again of the societal value of a sustained and robust support of our scientific enterprise.
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Science
Volume 372 | Issue 6538
9 April 2021
9 April 2021
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Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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RE: Does personalized immunity need to be monitored after COVID-19 vaccination?
To The Editor:
World Health Organization (WHO) has added Pfizer-BioNTech, Moderna, Sinovac, Sinopharm-BBIBP, Oxford–AstraZeneca and Janssen to list of safe and effective emergency tools against COVID-19. However, these vaccines lack effective evaluation in people with underlying medical conditions.
Oekelen et al. show that 15.8% multiple myeloma patients do not develop SARS-CoV-2 spike IgG antibody after completing the recommended two-dose Pfizer-BioNTech or Moderna mRNA vaccination regimen in 320 patients using FDA EUA COVID-SeroKlir Kantaro SARS-CoV-2 IgG Ab Kit, suggesting that the need for routine immunity monitoring of those patients following COVID-19 vaccination to allow for personalized risk reduction measures for vaccinated individuals (1).
Grupper et al. report 85 of 136 kidney transplant recipients (62.5%) have negative SARS-CoV-2 spike IgG antibody after administration of two-dose of Pfizer-BioNTech SARS-CoV-2 vaccine, suggesting that the personalized immunity need to be monitored after COVID-19 vaccination in kidney transplant recipients (2).
Rabinowich et al. have found 42 of 80 liver transplant recipients (52.5%) did not develop neutralizing antibody after administration of two-dose of the Pfizer-BioNTech BNT162b2 SARS CoV-2 vaccine, suggesting that FDA approved neutralizing antibody measures to the COVID-19 vaccine are urgently needed.
Kim et al. showed that comparing the Pfizer-BioNTech BNT162b2 vaccine with the SinoVac inactivated vaccine from health-care workers, the titer of the neutralizing antibody PRNT50 is 10 times different (4). In people who received the Pfizer-BioNTech BNT162b2 vaccine after the second dose, the neutralizing antibody PRNT50 titer was 269. In contrast, the people who received the SinoVac inactivated vaccine after the second dose, the neutralizing antibody PRNT50 titer was 27, indicating that people with inactivated vaccine might be monitored the neutralizing antibody more frequently after the vaccination.
Food and Drug Administration (FDA) has made recommendations for SARS-CoV-2 immunity testing, which can detect or correlate to SARS-CoV-2 neutralizing antibodies (5). Mount Sinai Laboratory (MSL) has received FDA EUA for use of the neutralization assay that has now been tested on over 30,000 patients (6, 7). The IgG neutralization test developed by MSL is also used for immunity assessment of Pfizer-BioNTech or Moderna vaccine (8).
In summary, FDA EUA approved SARS-CoV-2 neutralization test might be a valuable immunity evaluation test after the vaccination for people with underlying medical conditions or co-morbidities, such as cancer, chronic kidney & liver disease, diabetes, or immune deficiencies. The IgG neutralization test is the most effective tool to quickly assess the effectiveness of vaccination in different populations from different countries.
References
1. O. V. Oekelen et al. Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma. Cancer Cell. 39, 1028–1030 (2021).
2. A. Grupper et al. Reduced humoral response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus. Am. J. Transplant. 21, 2719-2726 (2021).
3. L. Rabinowich et al. Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients. J. Hepatol. 75, 435-438 (2021).
4. W. W. Lim et al. Comparative immunogenicity of mRNA and inactivated vaccines against COVID-19. Lancet Microbe. Published online June 15, 2021. https://doi.org/10.1016/S2666-5247(21)00177-4
5. Template for test developers of serology tests that detect or correlate to neutralizing antibodies. https://www.fda.gov/media/146746/download
6. Accelerated emergency use authorization (EUA) summary COVID-19 ELISA IgG antibody test (Mount Sinai Laboratory). https://www.fda.gov/media/137029/download
7. A. Wajnberg et al. Robust neutralizing antibodies to SARS-CoV-2 infection persist for months. Science. 370, 1227-1230 (2020).
8. F. Krammer et al. Antibody responses in seropositive persons after a single dose of SARS-CoV-2 mRNA vaccine. N. Engl. J. Med. 384, 1372-1374 (2021).
RE: Expanding the Narrative Behind the Development of COVID-19 Vaccines
There would be few medical specialists better placed anywhere to present an informative editorial on the historical development of any vaccines, including for COVID-19, than the Director of the National Institute of Allergy and Infectious Diseases, NIH.
The development of a variety of safe and effective vaccines at warp speed is unprecedented, being based on RNA platforms and adapted immunogens, but it might also be responsible for vaccine hesitation in the population, even among the highly educated.
Previous research on SARS (aka SARS-CoV-1) and MERS have enabled the development of vaccines at Moderna, Pfizer, and BioNTech.
There are many known unknowns, including the temporal durability of any vaccines, and their efficacy against the mutated strains, variants, and lineages of the original wild-type coronavirus (COVID-19), but these are currently under clinical investigation, probably at warp speed.
I have no competing interests.