CONFERENCE UPDATE : CROI 2020
COVID-19 vaccine: When will it be ready?
Coronavirus disease 2019 (COVID-19) continues to spread globally and place extreme pressures on healthcare systems, the economy and general society. One of the key questions circulating is: Will there be a vaccine? And if so, when? Although a definitive answer does not exist at present, there are many efforts underway in this space. Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases (NIAID), has said that the development of a COVID-19 vaccine is progressing rapidly. In a recorded message during a special session at the virtual Conference on Retroviruses and Opportunistic Infections (CROI), Dr. Fauci commented that the time from sequencing of the virus, which arose in central China in late December 2019, to human trials of a vaccine candidate is expected to move with an unprecedented speed.1,2
Why do we need a vaccine?
The disease caused by SARS-CoV-2 is called COVID-19, which has led to the deaths of over 35,000 people worldwide, with nearly 800,000 reported cases. It has maintained a foothold across the globe, reaching countries that already faced humanitarian crisis due to conflict, natural disasters and climate change.3 The World Health Organization (WHO) has warned that it will spread with unprecedented speed, and has suggested draconian containment measures.3 These containment measures have only managed to slow the spread of COVID-19, but at a huge economic and social cost.3
SARS-CoV-2 shares between 80% and 90% of its genetic material with the virus that caused SARS, hence its name.4 Both consist of a strip of ribonucleic acid (RNA) inside a spherical protein capsule that is covered in spikes.4 The spikes lock on to receptors on the surface of epithelial cells in the human lung, which allows the virus to enter the cell.4 Once inside, the virus hijacks the cell’s replication mechanisms to reproduce, before breaking out of the cell again and killing it in the process.4
There is concern that SARS-CoV-2, whose outbreak first emerged in Wuhan, China, in December 2019, may adapt to humans and evolve to be a human virus, leading to long term prevalence in humans and cause sporadic epidemics. Vaccination is thus considered the most effective way to stop an outbreak, prevent future pandemics, and alleviate the disease burden and mortality associated with infection.
About 35 companies and academic institutions are racing to create such a vaccine, with at least four who have identified candidates that have begun testing in animals.5 The first of these – produced by Boston-based biotech firm Moderna – will enter human trials imminently.5 Though nobody could have predicted that the next infectious disease to threaten the globe would be caused by a coronavirus, influenza is generally considered to pose the greatest pandemic risk. Vaccinologists had hedged their bets by working on “prototype” pathogens.5 “The speed with which we have [produced these candidates] builds very much on the investment in understanding how to develop vaccines for other coronaviruses,” said Dr. Fauci.5
Current efforts in the vaccine development
Dr. Fauci noted that it took 20 months to develop a candidate vaccine for the SARS-CoVs outbreak in 2003, 11 months to develop a vaccine candidate for the H5N1 influenza in 2006, 4 months for a vaccine candidate for the 2009 H1N1 influenza, and 3.5 months for the Zika virus vaccine in 2016. 2
He further added that the COVID-19 vaccine is a collaborative effort by the NIAID Vaccine Research Center, Moderna Therapeutics, and the Coalition for Epidemic Preparedness Innovations (CEPI). It is an mRNA vaccine candidate expressing the viral spike protein of COVID-19, Dr. Fauci explained. 2
Other potential COVID-19 vaccines in the works are a chimpanzee adenovirus-vectored candidate (NIAID Rocky Mountain Laboratories and Oxford University in the United Kingdom); a SARS recombinant protein candidate being evaluated for cross-neutralization (Baylor College of Medicine in Houston); and additional concepts such as recombinant spike vaccines, as well as other nucleic acid vaccine platforms.2
CEPI, based in Oslo, Norway, was set up to accelerate the development of vaccines against emerging infectious threats such as COVID-19. One of their approaches is to bridge the gap between public and private sectors to pool resources and expertise in order to jump start the vaccine development process. CEPI has been able to help establish and fund a consortium of leading vaccine developers, through their recent call for proposals, to harness a measles vector platform to develop a vaccine against COVID-19. In order to beat COVID-19, it is clear that an effective vaccine against SARS-CoV-2 is crucial. “By investing in a range of partners and vaccine technologies, we are giving ourselves the best chance of developing a vaccine that can stop COVID-19 in its tracks. We are calling on the international community to contribute to the fight against COVID-19 by investing in CEPI’s vaccine development programme, and help us deliver a long-term equitable solution to this unprecedented global challenge,” stated Dr. Richard Hatchett, Chief Executive Officer, CEPI.6
To date, CEPI has provided initial funding to Curevac, Inc., Inovio Pharmaceuticals, Inc., Moderna, Inc., Novavax, Inc., The University of Hong Kong (HKU), The University of Oxford, and The University of Queensland to develop COVID-19 vaccine candidates.
Vaccine based on weakened version of the flu virus
Scientists at the HKU have developed a vaccine candidate based on a weakened version of the influenza virus. It has been altered to express the surface protein of the SARS-CoV-2 virus; a method previously adopted in vaccine candidate development for Middle East respiratory syndrome. The collaborative effort with CEPI has enabled the HKU to begin preclinical testing of the vaccine candidate.1
The vaccine candidate is based on the established flu-based DelNS1 live attenuated influenza virus (LAIV) platform.7 Since it is a flu-based vaccine, it can be combined with any seasonal flu vaccine strains. Furthermore, it is a live attenuated vaccine, with the deletion of the key virulent element and immune antagonist, NS1, from the viral genome, which leads it to be potentially more immunogenic than the wild type influenza virus.7 This vaccine candidate can be easily produced in chicken embryonated eggs and MDCK cells, which are proven production systems for influenza vaccines.
Additionally, the use of a flu vector to express a specific antigen to induce immunity targeting the critical element of the Receptor Binding Domain (RBD) of SARS-CoVs, avoids potential antibody dependent enhancement (ADE) as observed in the experimental vaccine for SARS-CoV.7 Most importantly, it can be used as a nasal spray.7
President and Vice-Chancellor of the HKU, Professor Xiang Zhang commented, “I’m thankful for the support from CEPI. The HKU has outstanding researchers in emerging infectious diseases. I’m hopeful the vaccine being developed in our labs will contribute to the containment of COVID-19.”7
A measles vaccine vector
The Institut Pasteur are facilitating the development of a measles vaccine as a vector from which other recombinant vaccines can be designed to express antigens from other pathogens. "As part of the COVID-19 Task Force set up in January 2020, after our isolation of the coronavirus strains detected in France, the proprietary measles vector (MV) technology was chosen to develop a vaccine against SARS-CoV-2, leveraging our extensive experience with human measles vector technology and an MV-SARS-CoV-1 candidate," commented Stewart Cole, President of the Institut Pasteur.1
The MV is used as a vector from which recombinant vaccines can be designed to express antigens from other pathogens (Chikungunya virus, Lassa fever, MERS, human immunodeficiency virus dengue, West Nile, yellow fever, or other emerging diseases). In fact, the use of the modified MV as a vehicle for vaccination against these pathogens makes it possible to deliver the antigens directly into the compartments of the immune system capable of inducing a protective memory response.
An ongoing open-label trial
In January, the National Institutes of Health (NIH) and Moderna finalized the sequence for mRNA-1273, a vaccine against SARS-CoV-2. On March 16, the NIH announced the first participant in a phase 1 study of mRNA-1273. CEPI funded the manufacturing of the first batch of the vaccine, and the open-label trial is anticipated to recruit 45 healthy adult volunteers, providing data on the immunogenicity and safety of mRNA-1273.
"mRNA is an emerging platform. Over the past few years, we have demonstrated its potential in vaccines across more than 1,000 subjects in our clinical trials. This includes successful early-stage (Phase I) clinical trials against five other respiratory viruses (two pandemic influenza strains, RSV, hMPV, and PIV3). Over the last four years, we have started nine clinical trials for mRNA vaccines," Moderna said.1 The company emphasizes that it is still early in the process, but is preparing for a potential phase 2 study under an investigational new drug filing to build on the data from the ongoing phase 1 study.1
Accelerating vaccine development in critical times
The crucial element in the development of a vaccine against the SARS-CoV-2 is time, considering the continued spread of the virus and the increasing number of mortalities.
The clinical development of a vaccine for humans must follow the same general pathways as other drugs and biologics; including testing in pre-clinical models and eventually several phases of human clinical trials to determine efficacy, safety and dosage, amongst other parameters. These can take several years to conduct. However, in the current climate, collaborative efforts that are underway could fast track these timelines.1
Dr. Gregory Glenn MD, President of Research and Development at Novavax, explained, "Under normal circumstances, the development of a vaccine takes place via a well-structured schedule with set timelines for meetings with the Food and Drug Administration (FDA). In this context, the FDA are really collaborating with us to shorten the typical timeframes for certain conversations. We're hoping to have clinical trial data towards the end of summer which indicates that the vaccine is safe and that it triggers a functional immune response."1
Dr. J. Joseph Kim, Inovio's president and CEO shared an accelerated timeline at the United States (US) Coronavirus Task Force meeting in early March. The company began preclinical testing of INO-4800 in January, and plan to conduct human clinical trials in the US in April, which will be shortly followed by testing in China and South Korea. Kim said, "We plan on delivering one million doses by year end with existing resources and capacity."1
Moderna attribute their swift advances in developing mRNA-1273 to previous experience in the field, by stating, "We were able to leverage our experience in vaccines to move rapidly on design and manufacture of the materials for the phase 1 clinical trial. This included our broad understanding of the safety of our platform to date across more than 1,000 subjects."1
"Be under no illusion – vaccine development is tough"
It is clear that, as the world faces its worst public health crisis in a generation, scientists are striving full speed ahead on the frontline of vaccine development. The speed at which the space has progressed in just a few months is no doubt impressive, and the achievements made thus far are not to be underestimated. Dr. Hatchett emphasizes that the work being undertaken is far from easy, "Be under no illusion – vaccine development is tough. It is complex and costly, but CEPI was set-up specifically to overcome these challenges to rapidly develop vaccines against emerging infectious threats like the COVID-19 virus."1
Dr. Hatchett also pointed out, "There are no guarantee of success, but we are working flat out and, if all goes well, we are hoping that a safe and effective vaccine will begin to become available for individuals at greatest risk within the next 12-18 months."1
Although researchers are searching for effective and suitable vaccine candidates to control the deadly COVID-19, there are currently no effective vaccines for SARS-CoV-2. However, the ongoing, collaborative efforts and deep understanding of the disease and vaccine development process has sped up the manufacturing and testing process. As for now, we must rely exclusively on enforcing strict, preventive and control measures that minimize the risk of possible disease transmission.
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