COVID-19 vaccine



A COVID‑19 vaccine is a vaccine intended to provide acquired immunity against COVID‑19. Prior to the COVID‑19 pandemic, work to develop a vaccine against coronavirus diseases like SARS and MERS established knowledge about the structure and function of coronaviruses; this knowledge enabled accelerated development of various vaccine technologies during early 2020.

, 66 vaccine candidates are in clinical research, including 17 in Phase I trials, 23 in Phase I–II trials, 6 in Phase II trials, and 20 in Phase III trials. In Phase III trials, several COVID‑19 vaccines demonstrate efficacy as high as 95% in preventing symptomatic COVID‑19 infections. , ten vaccines are authorized by at least one national regulatory authority for public use: two RNA vaccines (the Pfizer–BioNTech vaccine and the Moderna vaccine), four conventional inactivated vaccines (BBIBP-CorV from Sinopharm, BBV152 from Bharat Biotech, CoronaVac from Sinovac, and WIBP from Sinopharm), three viral vector vaccines (Sputnik V from the Gamaleya Research Institute, the Oxford–AstraZeneca vaccine, and Ad5-nCoV from CanSino Biologics), and one peptide vaccine (EpiVacCorona from the Vector Institute).

Many countries have implemented phased distribution plans that prioritize those at highest risk of complications, such as the elderly, and those at high risk of exposure and transmission, such as healthcare workers. , 101.31million doses of COVID‑19 vaccine have been administered worldwide based on official reports from national health agencies. Pfizer, Moderna, and AstraZeneca predicted a manufacturing capacity of 5.3billion doses in 2021, which could be used to vaccinate about 3billion people (as the vaccines require two doses for a protective effect against COVID‑19). By December, more than 10billion vaccine doses had been preordered by countries, with about half of the doses purchased by high-income countries comprising 14% of the world's population.

Background
Prior to COVID‑19, a vaccine for an infectious disease had never been produced in less than several years—and no vaccine existed for preventing a coronavirus infection in humans. However, vaccines have been produced against several animal diseases caused by coronaviruses, including (as of 2003) 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 animals.

According to studies 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 at that time. As of 2020, there is no cure or protective vaccine proven to be safe and effective against SARS in humans. 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 PhaseI clinical trials in humans and three others in progress, all being viral-vectored vaccines: two adenoviral-vectored (ChAdOx1-MERS, BVRS-GamVac) and one MVA-vectored (MVA-MERS-S).

The urgency to create a vaccine for COVID‑19, led to compressed schedules that shortened the standard vaccine development timeline, in some cases combining clinical trial steps over months, a process typically conducted sequentially over years. Multiple steps along the entire development path are evaluated, including the level of acceptable toxicity of the vaccine (its safety), targeting vulnerable populations, the need for vaccine efficacy breakthroughs, the duration of vaccination protection, special delivery systems (such as oral or nasal, rather than by injection), dose regimen, stability and storage characteristics, emergency use authorization before formal licensing, optimal manufacturing for scaling to billions of doses, and dissemination of the licensed vaccine. Timelines for conducting clinical research – normally a sequential process requiring years – are being compressed into safety, efficacy, and dosing trials running simultaneously over months, potentially compromising safety assurance. As an example, Chinese vaccine developers and the government Chinese Center for Disease Control and Prevention began their efforts in January 2020, and by March were pursuing numerous candidates on short timelines, with the goal to showcase Chinese technology strengths over those of the United States, and to reassure the Chinese people about the quality of vaccines produced in China.

Planning and development
Since early 2020, vaccine development has been expedited via unprecedented collaboration in the multinational pharmaceutical industry and between governments. According to the Coalition for Epidemic Preparedness Innovations (CEPI), the geographic distribution of COVID‑19 vaccine development puts North American entities having about 40% of the activity compared to 30% in Asia and Australia, 26% in Europe, and a few projects in South America and Africa.

There have been several unique challenges with COVID-19 vaccine 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. Additionally, research at universities is obstructed by physical distancing and closing of laboratories.

Vaccines must progress through several phases of clinical trials to test for safety, immunogenicity, effectiveness, dose levels and adverse effects of the candidate vaccine. Vaccine developers have to invest resources internationally to find enough participants for PhaseII–III clinical trials when the virus has proved to be a "moving target" of changing transmission rate across and within countries, forcing companies to compete for trial participants; clinical trial organizers may encounter people unwilling to be vaccinated due to vaccine hesitancy or disbelieving the science of the vaccine technology and its ability to prevent infection. Even as new vaccines are developed during the COVID‑19 pandemic, licensure of COVID‑19 vaccine candidates requires submission of a full dossier of information on development and manufacturing quality.

Organizations
Internationally, the Access to COVID-19 Tools Accelerator is a G20 and World Health Organization initiative announced in April 2020. It is a cross-discipline support structure to enable partners to share resources and knowledge. It comprises four pillars, each managed by two to three collaborating partners: Vaccines (also called "COVAX"), Diagnostics, Therapeutics, and Health Systems Connector. The WHO's April 2020 "R&D Blueprint (for the) novel Coronavirus" documented a "large, international, multi-site, individually randomized controlled clinical trial" to allow "the concurrent evaluation of the benefits and risks of each promising candidate vaccine within 3–6 months of it being made available for the trial." The WHO vaccine coalition will prioritize which vaccines should go into Phase II and III clinical trials, and determine harmonized PhaseIII protocols for all vaccines achieving the pivotal trial stage.

National governments have also been involved in vaccine development. Canada announced funding for 96 research vaccine research projects at Canadian companies and universities, with plans to establish a "vaccine bank" that could be used if another coronavirus outbreak occurs, and to support clinical trials and develop manufacturing and supply chains for vaccines. China provided low-rate loans to a vaccine developer through its central bank and "quickly made land available for the company" to build production plants. Three Chinese vaccine companies and research institutes are supported by the government for financing research, conducting clinical trials, and manufacturing. Great Britain formed a COVID‑19 vaccine task force in April 2020 to stimulate local efforts for accelerated development of a vaccine through collaborations of industry, universities, and government agencies. It encompassed every phase of development from research to manufacturing. In the United States, the Biomedical Advanced Research and Development Authority (BARDA), a federal agency funding disease-fighting technology, announced investments to support American COVID‑19 vaccine development and manufacture of the most promising candidates. In May 2020, the government announced funding for a fast-track program called Operation Warp Speed.

Large pharmaceutical companies with experience in making vaccines at scale, including Johnson & Johnson, AstraZeneca, and GlaxoSmithKline (GSK), formed alliances with biotechnology companies, governments, and universities to accelerate progression to an effective vaccine.

Vaccine types


As of January 2021, nine different technology platforms – with the technology of numerous candidates remaining undefined – are under research and development to create an effective vaccine against COVID‑19. Most of the platforms of vaccine candidates in clinical trials are focused on the coronavirus spike protein and its variants as the primary antigen of COVID‑19 infection. Platforms being developed in 2020 involved nucleic acid technologies (nucleoside-modified messenger RNA and DNA), non-replicating viral vectors, peptides, recombinant proteins, live attenuated viruses, and inactivated viruses.

Many 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 COVID‑19 infection mechanisms. Vaccine platforms in development may improve flexibility for antigen manipulation and effectiveness for targeting mechanisms of COVID‑19 infection in susceptible population subgroups, such as healthcare workers, the elderly, children, pregnant women, and people with existing weakened immune systems.

RNA vaccines


An RNA vaccine contains RNA which, when introduced into a tissue, acts as messenger RNA (mRNA) to cause the cells to build the foreign protein and stimulate an adaptive immune response which teaches the body how to identify and destroy the corresponding pathogen or cancer cells. RNA vaccines often, but not always, use nucleoside-modified messenger RNA. The delivery of mRNA is achieved by a coformulation of the molecule into lipid nanoparticles which protect the RNA strands and help their absorption into the cells.

RNA vaccines were the first COVID-19 vaccines to be authorized in the United States and the European Union. As of January 2021, authorized vaccines of this type are the Pfizer-BioNTech COVID‑19 vaccine and the Moderna COVID-19 vaccine.

Adenovirus vector vaccines
These vaccines are examples of non-replicating viral vectors, using an adenovirus shell containing DNA that encodes a SARS‑CoV‑2 protein. The viral vector-based vaccines against COVID-19 are non-replicating, meaning that they do not make new virus particles, but rather produce only the antigen which elicits a systemic immune response.

As of January 2021, authorized vaccines of this type are the British Oxford–AstraZeneca COVID-19 vaccine, Russian Sputnik V, and Chinese Convidicea. Vaccines in clinical trials include Johnson & Johnson's Ad26.COV2.S.

Inactivated virus vaccines
Inactivated vaccines consist of virus particles that have been grown in culture and then are killed using a method such as heat or formaldehyde to lose disease producing capacity, while still stimulating an immune response.

As of January 2021, authorized vaccines of this type are the Chinese CoronaVac and BBIBP-CorV as well as the Indian Covaxin. Vaccines in clinical trials include the Valneva COVID-19 vaccine.

Subunit vaccines
Subunit vaccines present one or more antigens without introducing whole pathogen particles. The antigens involved are often protein subunits, but can be any molecule that is a fragment of the pathogen.

As of January 2021, the only authorized vaccine of this type is the peptide vaccine EpiVacCorona. Vaccines in clinical trials include the Novavax COVID-19 vaccine and RBD-Dimer. The V451 vaccine was previously in clinical trials, which were terminated because it was found that the vaccine may potentially cause incorrect results for subsequent HIV testing.

Other types
Additional types of vaccines that are in clinical trials include multiple DNA plasmid vaccines, at least two lentivirus vector vaccines,  a virus-like particle, and a vesicular stomatitis virus displaying the SARS‑CoV‑2 spike protein.

Scientists investigated whether existing vaccines for unrelated conditions could prime the immune system and lessen the severity of COVID‑19 infection. There is experimental evidence that the BCG vaccine for tuberculosis has non-specific effects on the immune system, but no evidence that this vaccine is effective against COVID‑19.

Trial and authorization status
PhaseI trials test primarily for safety and preliminary dosing in a few dozen healthy subjects, while PhaseII trials – following success in PhaseI – evaluate immunogenicity, dose levels (efficacy based on biomarkers) and adverse effects of the candidate vaccine, typically in hundreds of people. A PhaseI–II trial consists of preliminary safety and immunogenicity testing, is typically randomized, placebo-controlled, while determining more precise, effective doses. PhaseIII trials typically involve more participants at multiple sites, include a control group, and test effectiveness of the vaccine to prevent the disease (an "interventional" or "pivotal" trial), while monitoring for adverse effects at the optimal dose. Definition of vaccine safety, efficacy, and clinical endpoints in a PhaseIII trial may vary between the trials of different companies, such as defining the degree of side effects, infection or amount of transmission, and whether the vaccine prevents moderate or severe COVID‑19 infection.

A clinical trial design in progress may be modified as an "adaptive design" if accumulating data in the trial provide early insights about positive or negative efficacy of the treatment. Adaptive designs within ongoing PhaseII–III clinical trials on candidate vaccines may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, avoiding duplication of research efforts, and enhancing coordination of design changes for the Solidarity trial across its international locations.

Authorized and approved vaccines
National regulatory authorities have granted emergency use authorizations for nine vaccines. Three of those have been approved for emergency or full use by stringent regulatory authorities.

Efficacy
The effectiveness of a new vaccine is defined by its efficacy. In the case of COVID‑19, a vaccine efficacy of 67% may be enough to slow the pandemic, but this assumes that the vaccine confers sterilizing immunity, which is necessary to prevent transmission. Vaccine efficacy reflects disease prevention, a poor indicator of transmissibility of SARS‑CoV‑2 since asymptomatic people can be highly infectious. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) set a cutoff of 50% as the efficacy required to approve a COVID‑19 vaccine. As of 7 January, authorized and approved vaccines have shown efficacies ranging from 62–90% for the Oxford–AstraZeneca vaccine (various dosage regimens) to 95% for the Pfizer-BioNTech COVID‑19 vaccine. BBV152 has not published efficacy results as of 7 January. With BBIBP-CorV, Sinopharm announced a vaccine's efficacy was 79%, which was lower than the 86% announced by the United Arab Emirates (UAE) on 9 December. The UAE based its results on an interim analysis of Phase III trials conducted from July. With CoronaVac, after three delays in releasing results, Instituto Butantan announced in January 2021 that the vaccine was 78% effective in mild cases and 100% effective against severe and moderate infections based on 220 COVID‑19 cases from 13,000 volunteers. Butantan declined to elaborate how the efficacy rate was calculated. The efficacy of the Moderna COVID-19 Vaccine is 96% for those aged 18 to 64. The Novavax vaccine was found to be 89% effective in the UK.

SARS-CoV-2 variants
In mid-December 2020, a new SARS‑CoV‑2 variant (VOC-202012/01) was identified in the UK. While preliminary data indicates that this variant showed an estimated increase in reproductive number (R) by 0.4 or greater and increased transmissibility of up to 70%, there is as yet no evidence for lower vaccine effectiveness.

A South African variant (501.V2) has also emerged, which is believed to be more contagious.

Early results suggest that both the Pfizer and Moderna vaccines protect against the UK variant. However they are less effective against the South Africa variant, with Moderna reporting that the current vaccine produced only one-sixth of the antibodies in response to the South African variant compared with the original virus. They have launched a trial of a new vaccine to tackle the South African variant.

Formulation
, eleven of the vaccine candidates in clinical development use adjuvants to enhance immunogenicity. An immunological adjuvant is a substance formulated with a vaccine to elevate the immune response to an antigen, such as the COVID‑19 virus or influenza virus. Specifically, an adjuvant may be used in formulating a COVID‑19 vaccine candidate to boost its immunogenicity and efficacy to reduce or prevent COVID‑19 infection in vaccinated individuals. Adjuvants used in COVID‑19 vaccine formulation may be particularly effective for technologies using the inactivated COVID‑19 virus and recombinant protein-based or vector-based vaccines. Aluminum salts, known as "alum", were the first adjuvant used for licensed vaccines, and are the adjuvant of choice in some 80% of adjuvanted vaccines. The alum adjuvant initiates diverse molecular and cellular mechanisms to enhance immunogenicity, including release of proinflammatory cytokines.

Liability
On 4 February 2020, US Secretary of Health and Human Services Alex Azar published a notice of declaration under the Public Readiness and Emergency Preparedness Act for medical countermeasures against COVID‑19, covering "any vaccine, used to treat, diagnose, cure, prevent, or mitigate COVID‑19, or the transmission of SARS-CoV-2 or a virus mutating therefrom", and stating that the declaration precludes "liability claims alleging negligence by a manufacturer in creating a vaccine, or negligence by a health care provider in prescribing the wrong dose, absent willful misconduct". The declaration is effective in the United States through 1 October 2024.

In the European Union, the COVID‑19 vaccines are licensed under a Conditional Marketing Authorisation which does not exempt manufacturers from civil and administrative liability claims. While the purchasing contracts with vaccine manufacturers remain secret, they do not contain liability exemptions even for side-effects not known at the time of licensure.

Access
Nations pledged to buy doses of COVID-19 vaccine before the doses were available. Though high-income nations represent only 14% of the global population, as of 15 November 2020 they had contracted to buy 51% of all pre-sold doses. Some high-income nations bought more doses than would be necessary to vaccinate their entire populations.

On 18 January 2021, WHO Director-General Tedros Adhanom Ghebreyesus warned of problems with equitable distribution: "More than 39 million doses of vaccine have now been administered in at least 49 higher-income countries. Just 25 doses have been given in one lowest-income country. Not 25 million; not 25 thousand; just 25."

Vaccine hesitancy
Some 10% of the public perceives vaccines as unsafe or unnecessary, refusing vaccination – a global health threat called vaccine hesitancy – which increases the risk of further viral spread that could lead to COVID‑19 outbreaks. In mid-2020, estimates from two surveys were that 67% or 80% of people in the U.S. would accept a new vaccination against COVID‑19, with wide disparity by education level, employment status, race, and geography.

A poll conducted by National Geographic and Morning Consult demonstrated a gender gap on willingness to take a COVID‑19 vaccine in the U.S., with 69% of men polled saying they would take the vaccine, compared to only 51% of women. The poll also showed a positive correlation between education level and willingness to take the vaccine.

In an effort to demonstrate the vaccine's safety, prominent politicians have received it on camera, with others pledging to do so.