COVID-19 vaccine

For COVID-19 drug development, see COVID-19 drug development.

A COVID-19 vaccine is a hypothetical vaccine against coronavirus disease 2019 (COVID-19). Although no vaccine has completed clinical trials, there are multiple attempts in progress to develop such a vaccine. In late February 2020, the World Health Organization (WHO) said it did not expect a vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus, to become available in less than 18 months. The Coalition for Epidemic Preparedness Innovations (CEPI) – which is organizing a US$2 billion worldwide fund for rapid investment and development of vaccine candidates – indicated in April that a vaccine may be available under emergency use protocols by early 2021.

By April 2020, 115 vaccine candidates were in development, with two organizations having initiated Phase I-II safety and efficacy studies in human subjects. Five vaccine candidates were in Phase I safety studies in April.

2020 projects

COVID-19 was identified in December 2019. A major outbreak spread around the world in 2020, leading to considerable investment and research activity to develop a vaccine. Many organizations are using published genomes to develop possible vaccines against SARS-CoV-2. In the United States, the Food and Drug Administration announced its intent "to use all of the regulatory flexibility granted to it by Congress to ensure the most efficient and timely development of vaccines to fight COVID-19."

Some 79 companies and academic institutions are involved in vaccine development, with three of them receiving support from CEPI, including projects by the biotechnology companies Moderna, and Inovio Pharmaceuticals, and the University of Queensland. Five hundred clinical studies worldwide, across all stages of development on vaccine and therapeutic candidates for COVID-19, are registered with the World Health Organization Clinical Trial Registry, as of March 2020.

In early March 2020, CEPI announced a US$2 billion funding goal in a global partnership between public, private, philanthropic, and civil society organisations to accelerate development of COVID-19 vaccines, with commitments to date by the governments of Denmark, Finland, Germany, Norway, and the UK. Stated in April, imperatives of the CEPI initiative for vaccine development are speed, manufacturing capacity, deployment at scale, and global access.

Technology platforms

In April, CEPI scientists reported that 10 different technology platforms were under research and development during early 2020 to create an effective vaccine against COVID-19. Major platform targets advanced into Phase I safety studies include:

• nucleic acid (DNA and RNA) (Phase I developer and vaccine candidate: Moderna, mRNA-1273)
• viral vector (Phase I developer and vaccine candidate: CanSino Biologics, adenovirus type 5 vector)
• virus-like particle involved in DNA replication (Phase I developer and vaccine candidate: Shenzhen Geno-Immune Medical Institute, LV-SMENP)

According to CEPI, the platforms based on DNA or messenger RNA offer considerable promise to alter COVID-19 antigen functions for strong immune responses, and can be rapidly assessed, refined for long-term stability, and prepared for large-scale production capacity. Other platforms being developed in 2020 focus on peptides, recombinant proteins, live attenuated viruses, and inactivated viruses.

In general, the vaccine technologies being developed for COVID-19 are not like vaccines already in use to prevent influenza, but rather are using "next-generation" strategies for precision on the COVID-19 infection mechanisms, while hastening development for eventually preventing infection with a new vaccine. Vaccine platforms in development are also designed to address mechanisms for infection susceptibility to COVID-19 in specific population subgroups, such as the elderly, children, pregnant women, or people with existing weakened immune systems.

CEPI classifies development stages for vaccines as either "exploratory" (planning and designing a candidate, with no evaluation in vivo yet), "preclinical" (in vivo evaluation with preparation for manufacturing a compound to test in humans), or initiation of Phase I safety studies in healthy people.

Vaccine candidates

As reported by CEPI scientists in April, 115 total vaccine candidates are in early stages of development, with 78 confirmed as active projects (79, according to the Milken Institute), and 37 others announced, but with little public information available (presumed to be in planning or being designed). Of the 79 confirmed active projects, 74 are either in "exploratory" or "preclinical" development, according to the early-April CEPI report.

In April after the CEPI report was published, Phase I-II randomized, interventional trials for dosing and assessment for side effects began in Wuhan, China on the candidate vaccine, Ad5-nCoV (CanSino Biologics, table), and in England on the candidate, ChAdOx1 nCoV-19. Only five other trials on vaccine candidates are in Phase I human testing, as of mid-April.

Phase I trials test primarily for safety and preliminary dosing in a few dozen healthy subjects, while Phase II trials – following success in Phase I – evaluate immunogenicity, dose levels (efficacy based on biomarkers) and adverse effects of the candidate vaccine, typically in hundreds of people. A Phase I-II trial conducts preliminary safety and immunogenicity testing, is typically randomized, placebo-controlled, and at multiple sites, while determining more precise, effective doses. Phase III trials typically involve more participants, including a control group, and test effectiveness of the vaccine to prevent the disease, while monitoring for adverse effects at the optimal dose.

Clinical trials started in 2020

COVID-19: candidate vaccines in Phase I-II trials
Vaccine candidate (developer/sponsor)	Technology	Phase of trial (participants)	Location	Duration	References and notes
Ad5-nCoV (CanSino Biologics, Institute of Biotechnology of the Academy of Military Medical Sciences)	recombinant adenovirus type 5 vector	Phase II interventional trial for dosing and side effects (500)	Wuhan, China	March 2020 to December 2020
Ad5-nCoV (CanSino Biologics, Institute of Biotechnology of the Academy of Military Medical Sciences)	recombinant adenovirus type 5 vector	Phase I (108)	Wuhan, China	March 2020 to December 2020	continuing through 2020 during Phase II start
ChAdOx1 nCoV-19 (University of Oxford)	adenovirus vector	Phase I-II, randomized, placebo-controlled, multiple sites (510)	England, United Kingdom	April 2020 to May 2021
mRNA-1273 (Moderna, US National Institute of Allergy and Infectious Diseases)	lipid nanoparticle dispersion containing messenger RNA	Phase I (45)	United States	March 2020 to Spring-Summer 2021
Covid-19/aAPC (Shenzhen Geno-Immune Medical Institute)	lentiviral vector, pathogen-specific artificial antigen presenting dendritic cells	Phase I (100)	Shenzhen, China	March 2020 to 2023
LV-SMENP-DC (Shenzhen Geno-Immune Medical Institute)	lentiviral minigene vaccine, dendritic cells modified with lentiviral vector	Phase I (100)	Shenzhen, China	March 2020 to 2023
INO-4800 (Inovio Pharmaceuticals, CEPI)	DNA plasmid delivered by electroporation	Phase I (40)	United States	April 2020 to November 2020

Preclinical research

In April, the WHO issued a statement representing dozens of vaccine scientists around the world, pledging collaboration to speed development of a vaccine against COVID-19. International cooperation between organizations developing vaccine candidates, national regulatory and policy agencies, financial contributors, public health associations, and governments to coordinate on late-stage vaccine candidates for eventual manufacturing in sufficient vaccine quantities to supply all affected areas, particularly low-resource countries. Industry analysis of vaccine development historically show failure rates of about 84-90%. Because COVID-19 is a novel virus target with properties still being discovered and requiring innovative vaccine technologies and development strategies, the risks associated with developing a successful vaccine across all steps of preclinical and clinical research are high. To assess potential for vaccine efficacy, unprecedented computer simulations and COVID-19-specific animal models are being developed, but these methods remain untested by unknown characteristics of the COVID-19 virus, and are being organized multinationally during 2020.

In early April, CEPI scientists stated that 115 vaccine candidates were in development, as either "exploratory"/"preclinical" projects, or in Phase I safety trials in human participants. The table below derives from tracking public sources reporting the development progress of vaccine candidates – listing 87 projects as active in mid-April – with updates on the tracker every few days.

COVID-19: candidate vaccines scheduled for Phase I trials in 2020
Vaccine candidate (developer)	Technology	Start date announced
unnamed (Sinovac; Dynavax)	inactivated virus (formaldehyde inactivated + alum)	April
NVX-CoV2373 (Novavax)	protein subunit, nanoparticles	May
BNT162 (BioNTech; Fosun Pharma; Pfizer)	RNA	April-May
DPX-COVID-19 (IMV, Inc., Canadian Immunization Research Network)	protein subunit, lipid-based delivery	mid-2020
PittCoVacc (University of Pittsburgh)	protein subunit, microneedle arrays	mid-2020
unnamed (University of Cambridge)	protein subunit, S protein	mid-2020
unnamed (Imperial College London)	RNA; saRNA	mid-2020
CureVac (CEPI)	RNA, mRNA	mid-2020
LUNAR-COV19 (Arcturus Therapeutics, Duke University)	RNA, mRNA	mid-2020
unnamed (Sanofi Pasteur, GlaxoSmithKline)	protein subunit, S protein	mid-2020
unnamed (Cobra Biologics, Karolinska Institute)	DNA plasmid	mid-2020
unnamed (Medicago, Inc.)	plant-derived virus-like particle	July-August
CoroFlu (University of Wisconsin-Madison; FluGen; Bharat Biotech)	self-limiting influenza virus	Fall
unnamed (Janssen; Beth Israel Deaconess Medical Center)	non-replicating viral vector	September
unnamed (Takis; Applied DNA Sciences; Evvivax)	DNA	Fall
AdCOVID (Altimmune; University of Alabama at Birmingham)	non-replicating viral vector; intranasal	Fall
unnamed (Vaxart; Emergent BioSolutions)	non-replicating viral vector; oral	Fall
unnamed (VBI Vaccines; National Research Council of Canada)	pan-coronavirus	by year-end
Source: Milken Institute updated vaccine tracker

Supercomputer-assisted research

In March 2020, the US government, industry, and three universities pooled resources to access supercomputers from IBM, combined with cloud computing resources from Hewlett Packard Enterprise, Amazon, Microsoft, and Google. The COVID-19 High Performance Computing Consortium is being used to forecast disease spread, model possible vaccines, and screen thousands of chemical compounds to design a COVID-19 vaccine or therapy.

An additional consortium of Microsoft, six universities (including the Massachusetts Institute of Technology, a member of the first consortium), and the National Center for Supercomputer Applications in Illinois, working under the auspices of C3.ai, a company founded by billionaire software developer Thomas Siebel, are currently pooling their supercomputer resources for the same uses described above, along with developing medical protocols and strengthening public health strategies around the world, as well as awarding large grants to researchers who propose to use AI to carry out similar tasks by May. The consortium is called the C3.ai Digital Transformation Institute.

Non-specific vaccine

Some vaccines have heterologous effects, also called non-specific effects. That means they can have benefits beyond the disease they prevent. The anti-tuberculosis vaccine, BCG vaccine, is an example that is being tested to determine if it has a protective effect against COVID-19, pursuant to assertions that COVID-19 mortality was lower in countries having routine BCG vaccine administration.

In March 2020, a randomized trial of BCG vaccine to reduce COVID-19 illness began in the Netherlands, seeking to recruit 1,000 healthcare workers. A further randomized trial in Australia is seeking to enrol 4,170 healthcare workers. Another 700 healthcare workers from Boston and Houston will be recruited in another trial, and a further 900 healthcare workers in Egypt in a trial registered by a university in Cairo.

Potential limitations

It is possible vaccines in development will not be safe or effective. One study found that between 2006 and 2015, the success rate of obtaining approval from Phase I to successful Phase III trials was 16.2% for vaccines, and CEPI indicates a potential success rate of only 10% for vaccine candidates in 2020 development.

The rapid development and urgency of producing a vaccine for the COVID-19 pandemic may increase the risks and failure rate of delivering a safe, effective vaccine. Early research to assess vaccine efficacy using COVID-19-specific animal models, such as ACE2-transgenic mice, other laboratory animals, and non-human primates, indicate a need for biosafety-level 3 containment measures for handling live viruses, and international coordination to ensure standardized safety procedures. An April 2020 CEPI report stated: "strong international coordination and cooperation between vaccine developers, regulators, policymakers, funders, public health bodies and governments will be needed to ensure that promising late-stage vaccine candidates can be manufactured in sufficient quantities and equitably supplied to all affected areas, particularly low-resource regions."

While the flu vaccine is typically mass-produced by injecting the virus into the eggs of chickens, this method will not work for the COVID-19 vaccine, as the SARS-CoV-2 virus cannot replicate inside eggs.

Controversy of "challenge" studies

During the global emergency of the COVID-19 pandemic, strategies are under consideration to fast-track the timeline for licensing a vaccine against COVID-19, especially by compressing (to a few months) the usually lengthy duration of Phase II-III trials (typically, many years). Following preliminary proof of safety and efficacy of a candidate vaccine in laboratory animals and healthy humans, controlled "challenge" studies may be implemented to bypass typical Phase III research, providing an accelerated path to license a vaccine for widespread prevention against COVID-19. Challenge studies have been implemented previously for diseases less deadly than COVID-19 infection, such as common influenza, typhoid fever, cholera, and malaria.

The design of a challenge study involves first, simultaneously testing a vaccine candidate for immunogenicity and safety in laboratory animals and healthy adult volunteers (100 or fewer) – which is usually a sequential process using animals first – and second, rapidly advancing its effective dose into a large-scale Phase II-III trial in previously-uninfected, low-risk volunteers (such as young adults), who would then be deliberately infected with COVID-19 for comparison with a placebo control group. Following the challenge, the volunteers would be monitored closely in clinics with life-saving resources, if needed. Volunteering for a vaccine challenge study during the COVID-19 pandemic is likened to the emergency service of healthcare personnel for COVID-19-infected people, firefighters, or organ donors.

Although challenge studies are ethically questionable due to the unknown hazards for the volunteers of possible COVID-19 disease enhancement and whether the vaccine received has long-term safety (among other cautions), challenge studies may be the only option available as the COVID-19 pandemic worsens, according to some infectious disease experts, to rapidly produce an effective vaccine that will minimize the projected millions of deaths worldwide from COVID-19 infection.

History

Vaccines have been produced against several diseases caused by coronaviruses for animal use, including for infectious bronchitis virus in birds, canine coronavirus and feline coronavirus.

Previous projects to develop vaccines for viruses in the family Coronaviridae that affect humans have been aimed at severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Vaccines against SARS and MERS have been tested in non-human animal models. As of 2020, there is no cure or protective vaccine for SARS that has been shown to be both safe and effective in humans. According to research papers published in 2005 and 2006, the identification and development of novel vaccines and medicines to treat SARS was a priority for governments and public health agencies around the world.

There is also no proven vaccine against MERS. When MERS became prevalent, it was believed that existing SARS research may provide a useful template for developing vaccines and therapeutics against a MERS-CoV infection. As of March 2020, there was one (DNA based) MERS vaccine which completed phase I clinical trials in humans, and three others in progress, all of which are viral-vectored vaccines, two adenoviral-vectored (ChAdOx1-MERS, BVRS-GamVac), and one MVA-vectored (MVA-MERS-S).

Misinformation

Main article: Misinformation related to the 2019–20 coronavirus pandemic

Social media posts have promoted a conspiracy theory claiming the virus behind COVID-19 was known and that a vaccine was already available. The patents cited by various social media posts reference existing patents for genetic sequences and vaccines for other strains of coronavirus such as the SARS coronavirus.

See also

• 2019–20 coronavirus pandemic
• Coronavirus disease 2019
• Severe acute respiratory syndrome coronavirus 2
• 2009 flu pandemic vaccine
• Respiratory disease
• COVID-19 drug development
• Phases of clinical research

External links

• "COVID-19 Vaccine Tracker". Regulatory Focus.