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The genetic sequence of SARS-CoV-2, the coronavirus that causes COVID-19, was published on 11 January 2020, triggering intense global R&D activity to develop a vaccine against the disease. The scale of the humanitarian and economic impact of the COVID-19 pandemic is driving evaluation of next-generation vaccine technology platforms through novel paradigms to accelerate development, and the first COVID-19 vaccine candidate entered human clinical testing with unprecedented rapidity on 16 March 2020.
The Coalition for Epidemic Preparedness Innovations (CEPI) is working with global health authorities and vaccine developers to support the development of vaccines against COVID-19. To facilitate this effort, we have developed and are continuously maintaining an overview of the global landscape of COVID-19 vaccine development activity. Our landscape database includes vaccine development programmes reported through the WHO’s authoritative and continually updated list, along with other projects identified from publicly available and proprietary sources (see Supplementary Box 1). The landscape provides insights into key characteristics of COVID-19 vaccine R&D and serves as a resource for ongoing portfolio management at CEPI. We have also shared our landscape information with others in the global health ecosystem to help improve coordination in the COVID-19 outbreak response and enable global resources and capabilities to be directed towards the most promising vaccine candidates.
COVID-19 vaccine R&D landscape
As of 8 April 2020, the global COVID-19 vaccine R&D landscape includes 115 vaccine candidates (Fig. 1), of which 78 are confirmed as active and 37 are unconfirmed (development status cannot be determined from publicly available or proprietary information sources). Of the 78 confirmed active projects, 73 are currently at exploratory or preclinical stages. The most advanced candidates have recently moved into clinical development, including mRNA-1273 from Moderna, Ad5-nCoV from CanSino Biologicals, INO-4800 from Inovio, and LV-SMENP-DC and pathogen-specific aAPC from Shenzhen Geno-Immune Medical Institute (Table 1). Numerous other vaccine developers have indicated plans to initiate human testing in 2020.
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Investigational vaccine protects monkeys against COVID-19 pneumonia
A single dose of ChAdOx1 nCoV-19, an investigational vaccine against SARS-CoV-2, has protected six rhesus macaques from pneumonia caused by the virus, according to National Institutes of Health scientists and University of Oxford collaborators. SARS-CoV-2 is the virus that causes COVID-19. The researchers posted their data to the preprint server bioRxiv. The findings are not yet peer-reviewed but are being shared to assist the public health response to COVID-19. Based on these data, a Phase 1 trial of the candidate vaccine began on April 23 in healthy volunteers in the United Kingdom.
"Vaccine technology has significantly evolved in the last decade, including the development of several RNA and DNA vaccine candidates, licensed vectored vaccines (e.g., Ervebo, a vesicular stomatitis virus [VSV]-vectored ebolavirus vaccine, licensed in the European Union), recombinant protein vaccines (e.g., Flublok, an influenza virus vaccine made in insect cells, licensed in the United States), and cell-culture-based vaccines (e.g., Flucelvax, an influenza virus vaccine made in mammalian cells). SARS-CoV-2 was identified in record time, and its genomic sequence was swiftly made widely available by Chinese researchers (Wu et al., 2020, Zhou et al., 2020, Zhu et al., 2020). In addition, we know from studies on SARS-CoV-1 and the related MERS-CoV vaccines that the S protein on the surface of the virus is an ideal target for a vaccine. In SARS-CoV-1 and SARS-CoV-2, this protein interacts with the receptor ACE2, and antibodies targeting the spike can interfere with this binding, thereby neutralizing the virus (Figure 1). The structure of the S protein of SARS-CoV-2 was solved in record time at high resolution, contributing to our understanding of this vaccine target (Lan et al., 2020a, Wrapp et al., 2020). Therefore, we have a target antigen that can be incorporated into advanced vaccine platforms.
Figure 1. Overview of Potential SARS-CoV-2 Vaccine Platforms
The structure of a coronavirus particle is depicted on the left, with the different viral proteins indicated. The S protein is the major target for vaccine development. The spike structure shown is based on the trimeric SARS-CoV-1 spike (PDB: 5XL3). One trimer is shown in dark blue, and the receptor binding domain, a main target of neutralizing antibodies, is highlighted in purple. The other two trimers are shown in light blue. SARS-CoV-2 vaccine candidates based on different vaccine platforms have been developed, and for some of them, pre-clinical experiments have been initiated. For one mRNA-based candidate, a clinical trial recently started to enroll volunteers shortly (ClinicalTrials.gov: NCT04283461). However, many additional steps are needed before these vaccines can be used in the population, and this process might take months, if not years. 1For some candidates, cGMP processes have already been established. 2Clinical trial design might be altered to move vaccines through clinical testing quicker.
Several vaccines for SARS-CoV-1 were developed and tested in animal models, including recombinant S-protein-based vaccines, attenuated and whole inactivated vaccines, and vectored vaccines (Roper and Rehm, 2009). Most of these vaccines protect animals from challenge with SARS-CoV-1, although many do not induce sterilizing immunity. In some cases, vaccination with the live virus results in complications, including lung damage and infiltration of eosinophils in a mouse model (e.g., Bolles et al., 2011, Tseng et al., 2012) and liver damage in ferrets (e.g., Weingartl et al., 2004). In another study, vaccination with inactivated SARS-CoV-1 led to enhancement of disease in one NHP, whereas it protected 3 animals from challenge (Wang et al., 2016). The same study identified certain epitopes on the S protein as protective, whereas immunity to others seemed to be enhancing disease. However, in almost all cases, vaccination is associated with greater survival, reduced virus titers, and/or less morbidity compared with that in unvaccinated animals. Similar findings have been reported for MERS-CoV vaccines (Agrawal et al., 2016, Houser et al., 2017). Therefore, whereas vaccines for related coronaviruses are efficacious in animal models, we need to ensure that the vaccines, which are developed for SARS-CoV-2, are sufficiently safe.
Another consideration for effective coronavirus vaccine development might be waning of the antibody response. Infection with human coronaviruses does not always induce long-lived antibody responses, and re-infection of an individual with the same virus is possible after an extended period of time (but only in a fraction of individuals and resulting in mild or no symtpoms), as shown in human challenge studies (Callow et al., 1990). Antibody titers in individuals that survived SARS-CoV-1 or MERS-CoV infections often waned after 2–3 years (Liu et al., 2006, Wu et al., 2007) or were weak initially (Choe et al., 2017). Despite that, re-infections are unlikely in the short term. Of note, re-infections after days of recovery have been reported recently but appear to be the consequences of false negative test results (Lan et al., 2020b). However, they could happen when humoral immunity wanes over months and years. An effective SARS-CoV-2 vaccine will need to overcome these issues to protect in a scenario in which the virus becomes endemic and causes recurrent seasonal epidemics.
SARS-CoV-2 infection causes the most severe pathology in individuals above 50 years of age. The reason for this is not clear, but many viral infections have milder manifestations in naive younger individuals than in naive older individuals. Because older individuals are more affected, it will be important to develop vaccines that protect this segment of the population. Unfortunately, older individuals typically respond less well to vaccination because of immune senescence (Sambhara and McElhaney, 2009). For influenza, which is problematic for older adults, specific formulations for this segment of the population include more antigen or an adjuvant (DiazGranados et al., 2013, Tsai, 2013). Protection in older individuals appears to require higher neutralization titers against influenza virus than in younger individuals (Benoit et al., 2015), and this issue might need to be addressed for SARS-CoV-2. If vaccination in older individuals is not effective, they could still benefit indirectly if vaccination is able to stop transmission of the virus in younger individuals.
Only a small number of SARS-CoV-1 vaccines made it to phase I clinical trials before funding dried up because of eradication of the virus from the human population through non-pharmaceutical interventions when case numbers were still small. Results from these trials, performed with an inactivated virus vaccine and a spike-based DNA vaccine, are encouraging because the vaccines were safe and induced neutralizing antibody titers (Lin et al., 2007, Martin et al., 2008). Some neutralizing monoclonal antibodies isolated against SARS-CoV-1, like CR3022 (ter Meulen et al., 2006, Tian et al., 2020), can cross-react to the receptor binding domain of SARS-CoV-2. This suggests that SARS-CoV-1 vaccines might cross-protect against SARS-CoV-2. However, because these vaccines have not been developed further than phase I, they are currently not available for use. Vaccines against MERS-CoV, also targeting the MERS-CoV S protein, are in pre-clinical and clinical development, including vaccines based on modified vaccinia Ankara vectors, adenovirus vectors, and DNA-based vaccines, and several of them are supported by the Coalition for Epidemic Preparedness Innovation (CEPI) (Yong et al., 2019). However, it is unlikely that MERS-CoV vaccines induce strong cross-neutralizing antibodies to SARS-CoV-2 because of the phylogenetic distance between the two viruses. Nevertheless, we can still learn a lot from these vaccines about how to move forward with SARS-CoV-2 vaccine design (Pallesen et al., 2017).
The Current Pipeline for SARS-CoV-2 Vaccines
The development of vaccines for human use can take years, especially when novel technologies are used that have not been extensively tested for safety or scaled up for mass production. Because no coronavirus vaccines are on the market and no large-scale manufacturing capacity for these vaccines exists as yet (Table 1), we will need to build these processes and capacities. Doing this for the first time can be tedious and time consuming (Figure 1). CEPI has awarded funds to several highly innovative players in the field, and many of them will likely succeed in eventually making a SARS-CoV-2 vaccine. However, none of these companies and institutions have an established pipeline to bring such a vaccine to late-stage clinical trials that allow licensure by regulatory agencies, and they do not currently have the capacity to produce the number of doses needed. An mRNA-based vaccine, which expresses target antigen in vivo in the vaccinee after injection of mRNA encapsulated in lipid nanoparticles, co-developed by Moderna and the Vaccine Research Center at the National Institutes of Health, is currently the furthest along, and a phase I clinical trial recently started (ClinicalTrials.gov: NCT04283461). Curevac is working on a similar vaccine but is still in the pre-clinical phase. Additional approaches in the pre-clinical stage include recombinant-protein-based vaccines (focused on the S protein, e.g., ExpresS2ion, iBio, Novavax, Baylor College of Medicine, University of Queensland, and Sichuan Clover Biopharmaceuticals), viral-vector-based vaccines (focused on the S protein, e.g., Vaxart, Geovax, University of Oxford, and Cansino Biologics), DNA vaccines (focused on the S protein, e.g., Inovio and Applied DNA Sciences), live attenuated vaccines (Codagenix with the Serum Institute of India, etc.), and inactivated virus vaccines (Figure 1; Table 1). All of these platforms have advantages and disadvantages (Table 1), and it is not possible to predict which strategy will be faster or more successful. Johnson & Johnson (J&J) (Johnson & Johnson, 2020) and Sanofi (2020) recently joined efforts to develop SARS-CoV-2 vaccines. However, J&J is using an experimental adenovirus vector platform that has not yet resulted in a licensed vaccine. Sanofi’s vaccine, to be made using a process similar to the process used for their approved Flublok recombinant influenza virus vaccine (Zhou et al., 2006), is also months, if not years, from being ready for use in the human population."
Soluble human ACE2 can inhibit SARS-CoV-2 infections
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SARS-CoV-2 can directly infect human blood vessel and kidney organoids
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Human organoids as model systems to study SARS-CoV-2 infections/COVID-19
Summary
We have previously provided the first genetic evidence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000–5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.
Dexamethasone, a steroid in use for decades, reduced deaths of COVID-19 patients on ventilators by about a third compared with standard care, researchers reported in a news release June 16. Deaths of COVID-19 patients on supplemental oxygen were reduced by about 20 percent.
If the results hold up to scrutiny once scientists have a chance to review the full data, the drug would be the first to reduce the risk of death from the disease, Tina Hesman Saey reports.
Although the results are important for treating the sickest patients with COVID-19, those patients represent only about 5 percent of people diagnosed with the coronavirus, says Rajesh Gandhi, an infectious diseases doctor at Massachusetts General Hospital and Harvard Medical School in Boston, who wasn’t involved in the new research. “It’s not steroids for all.” Read more
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MAY 18, 2020
Investigational vaccine protects monkeys against COVID-19 pneumonia
A single dose of ChAdOx1 nCoV-19, an investigational vaccine against SARS-CoV-2, has protected six rhesus macaques from pneumonia caused by the virus, according to National Institutes of Health scientists and University of Oxford collaborators. SARS-CoV-2 is the virus that causes COVID-19. The researchers posted their data to the preprint server bioRxiv. The findings are not yet peer-reviewed but are being shared to assist the public health response to COVID-19. Based on these data, a Phase 1 trial of the candidate vaccine began on April 23 in healthy volunteers in the United Kingdom.
Scientists are discovering that infected asymptomatic people have a lower immune response than do symptomatic people. It makes sense because the SARS-CoV-2 has the ability to hide from the body's antiviral immune response and therefore the immune response does not sense the danger until it is almost too late. It correlates like a surprise attack during a war where the body is quietly infiltrated by the virus and when the body's immune system finally discovers the danger, and mounts an immune counter attack, it does more harm than good! Too many infected cells are destroyed along with the virus. The virus has quietly infiltrated every cell in the lungs and the lungs are destroyed by the immune system in an attempt to kill the virus.
The Covid-19 virus is sneaky and because a person is asymptomatic does not mean he or she is not infected. If a person is infected and feels nothing, that may be because the virus is incubating and hiding from the immune system. We absolutely need early testing to discover who is infected and who is not infected. All infected people need a vaccine to help the body identify the virus and stimulate an early immune response that does no harm except to the virus. Some vaccines now in the works will not do damage to the human cell host.
Vaccines are now being created by several companies around the world and it will not be long before all Corona viruses will be eradicated from our lives.
There are as yet no licenced therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric Spike whose receptor binding domain (RBD) recognises angiotensin-converting enzyme 2 (ACE2), initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralising SARS-CoV-2 and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilising, CR3022 epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryo-EM analysis confirms that incubation of Spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope may be useful therapeutically, possibly in synergy with an antibody blocking receptor attachment.
GENTLE PEOPLE: Scientists are discovering that infected asymptomatic people have a lower immune response than do symptomatic people. It makes sense because the SARS-CoV-2 has the ability to hide from the body's antiviral immune response and therefore the immune response does not sense the danger until it is almost too late. It correlates like a surprise attack during a war where the body is suddenly over-whelmed by the virus and then attempts to fight back only to cause more damage. When it finally discovers the danger the immune system creates a large counter-attack creating a dangerous response which does more harm than good. Too many infected cells are destroyed along with the virus. The virus has quietly infiltrated every cell in the lungs and the lungs are destroyed by the immune system in an attempt to kill the virus.
The Covid-19 virus is sneaky and because a person is asymptomatic does not mean he or she is not infected. If a person is infected and feels nothing, that may be because the virus is incubating and hiding from the immune system. We absolutely need early testing to discover who is infected and who is not infected. All infected people need a vaccine to help the body identify the virus and stimulate an early immune response that does no harm except to the virus. Some vaccines now in the works will not do damage to the human cell host.
Vaccines are now being created by several companies around the world and it will not be long before all Corona viruses will be eradicated from our lives.
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