COVID-19 Vaccine Developments: Emerging Technologies, Safety Concerns and Antibody-Dependent Enhancement

COVID-19 Vaccine Developments: Emerging Technologies, Safety Concerns and Antibody-Dependent Enhancement

Friday, June 12, 2020

Since the SARS-CoV-2 genome had been sequenced, researchers around the globe have been racing to develop a vaccine for COVID-19. Traditional vaccine development can take up to 10 years to produce a safe and effective vaccine. Due to the obvious safety concerns presented by the novel coronavirus (SARS-CoV-2), vaccine development has been deemed paramount to global security, and timelines for an effective vaccine are estimated to be 12-18 months. There are nearly 100 vaccine candidates under review at this very moment, however, many are still at the conceptual stage. Leading the pack are several promising vaccines in clinical trials, whose rapid development may very well reach completion under the 18-month timeline. Two questions stand out as many follow the vaccine race: how are scientists cutting down on so much development time and will the reduction in development ensure a safe vaccine? We will address these questions while learning who is leading the race in developing these vaccines, their development strategies, and the safety concerns researchers are addressing throughout manufacturing.

Established Vaccine Technologies

Several companies are utilizing established technologies to develop their vaccines. GlaxoSmithKline and Sanofi are working together using a protein subunit approach. The vaccine consists of the spike antigen combined with an adjuvant. They are aiming to begin a phase 1 trial by the end of the year. Other companies are using the whole SARS-CoV-2 virus, which is weakened or destroyed1.

Emerging Technologies

In order to meet the aggressive development schedule, some companies are using emerging technologies. Moderna’s mRNA-1273 candidate utilizes nucleotide-based vaccine development. Here, a synthetic lipid nanoparticle is used to carry mRNA templates with the goal of getting the immune system to recognize SARS-CoV-2’s spike protein.

AstraZeneca and the University of Oxford are working together to develop AZD1222, a recombinant vaccine, engineered from a chimpanzee adenovirus to transport DNA for the spike antigen.

Both technologies have yet to produce a vaccine that has been approved in the EU or USA before, however, both technologies have shown substantial promise during SARS-CoV-2 vaccine development1.

Safety Concerns

The rapid development of these vaccines has raised concerns regarding vaccine safety. Normal development can be up to 10 years and the typical success rate for vaccine development is roughly 6%. Traditionally, a significant amount of time is used to evaluate both the short-term and long-term safety of the vaccine. Data collection issues are typical to vaccine development as older (and infant) populations, with weakened immune systems, may respond differently to the vaccine than young to matured adult populations1. Time is necessary to flush out these conclusions and determine the correct courses of action to optimize safety and efficacy during development. Additionally, antibody-dependent enhancement could lead to exacerbation of the disease. Again, time and further research are needed to evaluate the concerns.

Antibody-Dependent Enhancement (ADE)

Perhaps the most popular example of Antibody-Dependent Enhancement (ADE) is Dengue fever. Affecting over 100 million new infections and 40,000 deaths annually, Dengue fever is prominent in tropical environments. The Dengue virus has four serotypes, all of which support protective immunity2. Homotypic protection has demonstrated long-lasting protection, but cross-neutralizing antibodies against different serotypes are relatively short in duration (lasting up to 2 years)3. Reinfection with a different serotype becomes dangerous when protective antibody titer’s decrease. Non-neutralizing antibodies replace neutralizing antibodies and bind to Dengue fever virions forming a complex with the immune system’s phagocytic cells, and subsequently mediate infection. In low neutralizing antibody concentrations, heterotypic antibodies lead to ADE in patients infected with a different serotype of the virus4.

Researchers demonstrated that there was an increased risk of a severe course of Dengue fever if the patient had low titers of antibodies from a previous Dengue infection5. During Vaccine Development for Dengue fever, researchers observed this same phenomenon. The vaccine was approved for efficacy trials in 20156. Upon evaluation of follow up data from the vaccine trial, it was determined that after 3 years children (9 years older and younger) had higher hospitalization rates in vaccine recipients than controls. ADE is proposed as the likely mechanism, as the vaccine was mimicking the primary infection. After enough time had passed the patient’s immunity had decreased enough to become vulnerable to ADE with exposure of a secondary infection7.

SARS-CoV, SARS-CoV-2 and ADE

ADE has been reported for severe acute respiratory syndrome (SARS). Researchers found antibodies elicited by a SARS-CoV vaccine enhanced infection of B cell lines in a hamster model8.

In a macaque model of SARS, scientists discovered that the wound-healing response reflected a proinflammatory profile, in macrophages entering the lungs, associated with the presence of anti-spike IgG9. These observations were observed by patients deceased of SARS, according to the Authors. It has been proposed that Fc receptors of anti-SARS-CoV antibodies bound with virions may produce ADE, and lead to enhanced viral cell entry and replication.

There has not been a confirmation that SARS-CoV-2 (novel coronavirus) has the same ADE risks as SARS-CoV. However, cross-reactivity of antibodies against the spike protein of SARS-CoV and SARS-CoV-2 is prevalent, and recent research claims they are rarely cross-neutralizing10. Given the potential for similar behavior, significant resources, and time will be needed to properly evaluate SARS-CoV-2 vaccine development. As pressure continues to advance the race for a vaccine, researchers must ensure that all safety considerations be addressed to ensure optimal vaccine outcomes.

Chris Cicinelli is the Editor and Science Writer for Labcompare and American Laboratory. 

References

  1. Mullard, Asher. “COVID-19 vaccine development pipeline gears up”. June 06, 2020. DOI: https://doi.org/10.1016/S0140-6736(20)31252-6
  2. Roth GA, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi NGBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736–88. [doi:.]. http://dx.doi.org/10.1016/S0140-6736(18)32203-7 PubMed
  3. Montoya M, Gresh L, Mercado JC, Williams KL, Vargas MJ, Gutierrez GSymptomatic versus inapparent outcome in repeat dengue virus infections is influenced by the time interval between infections and study year. PLoS Negl Trop Dis. 2013;7(8):e2357. [doi:.]. http://dx.doi.org/10.1371/journal.pntd.0002357 PubMed
  4. Katzelnick LC, Montoya M, Gresh L, Balmaseda A, Harris E. Neutralizing antibody titers against dengue virus correlate with protection from symptomatic infection in a longitudinal cohort. Proc Natl Acad Sci USA. 2016;113(3):728–33. [doi:.]. http://dx.doi.org/10.1073/pnas.1522136113 PubMed
  5. Endy TP, Nisalak A, Chunsuttitwat S, Vaughn DW, Green S, Ennis FARelationship of preexisting dengue virus (DV) neutralizing antibody levels to viremia and severity of disease in a prospective cohort study of DV infection in Thailand. J Infect Dis. 2004;189(6):990–1000. [doi:.]. http://dx.doi.org/10.1086/382280 PubMed
  6. who.int. [Internet]. Immunization, Vaccines and Biologicals. Questions and Answers on Dengue Vaccines [cited 2020 Apr 9]. Available from: https://www.who.int/immunization/research/development.
  7. Hadinegoro SR, Arredondo-García JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R. Efficacy and long-term safety of a Dengue vaccine in regions of endemic disease. N Engl J Med. 2015;373(13):1195–206. [doi:.]. http://dx.doi.org/10.1056/NEJMoa1506223 PubMed
  8. Kam YW, Kien F, Roberts A, Cheung YC, Lamirande EW, Vogel LAntibodies against trimeric S glycoprotein protect hamsters against SARS-CoV challenge despite their capacity to mediate FcgammaRII-dependent entry into B cells in vitro. Vaccine. 2007;25(4):729–40. [doi:.]. http://dx.doi.org/10.1016/j.vaccine.2006.08.011 PubMed
  9. Liu L, Wei Q, Lin Q, Fang J, Wang H, Kwok HAnti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight. 2019;4(4):e123158. [doi:.]. http://dx.doi.org/10.1172/jci.insight.123158 PubMed
  10. Lv N, Wu NC, Tsang OTY, Yuan M, Perera RAPM, Leung WS, et al. Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections. BioRxiv 2020.03.15.993097 [Preprint]. 2020 [posted 2020 March 17, cited 2020 April 9]. Available from: https://www.biorxiv.org/content/10.1101/2020.03.15.993097v1
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