John P. Sadowski (NIOSH): /* Trials */ image moved from COVID-19 vaccine
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After a coronavirus was isolated in December 2019,<ref name="who-time" /> its [[Nucleic acid sequence|genetic sequence]] was published on 11 January 2020, triggering an urgent international response to prepare for an outbreak and hasten development of a preventive vaccine.<ref name="thanh3" /><ref name="gates1" /><ref name="Fauci" /> Since early 2020, [[COVID-19 vaccine]] development has been expedited via unprecedented collaboration in the [[Pharmaceutical industry|multinational pharmaceutical industry]] and between governments.<ref name="thanh22" /> By June 2020, tens of billions of dollars were invested by corporations, governments, international health organizations, and university research groups to develop dozens of vaccine candidates and prepare for global vaccination programs to immunize against COVID‑19 infection.<ref name="gates1" /><ref name="hbr" /><ref name="cbcr" /><ref name="ahmed" /> 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.<ref name="thanh22" /><ref name="thanh3" />
In February 2020, the 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.<ref name=":0" /> The rapidly growing infection rate of COVID‑19 worldwide during early 2020 stimulated international alliances and government efforts to urgently organize resources to make multiple vaccines on shortened timelines,<ref name="who-accel" /> with four vaccine candidates entering human evaluation in March (see the table of [[COVID-19 vaccine#Clinical trials started in 2020|clinical trials started in 2020]], below).<ref name="thanh3" /><ref name="yamey" />
On 24 June 2020, China approved the CanSino vaccine for limited use in the military and two inactivated virus vaccines for emergency use in high-risk occupations.<ref name=":1">Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 11 August 2020, Russia announced the approval of its Sputnik V vaccine for emergency use, though one month later only small amounts of the vaccine had been distributed for use outside of the phase 3 trial.<ref name=":2">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
The Pfizer-BioNTech partnership submitted an EUA request to the FDA for the mRNA vaccine BNT162b2 (active ingredient [[tozinameran]]) on 20 November 2020.<ref name=":3">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name=":4">Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 2 December 2020, the United Kingdom's [[Medicines and Healthcare products Regulatory Agency]] (MHRA) gave temporary regulatory approval for the [[Pfizer-BioNTech COVID‑19 vaccine|Pfizer–BioNTech vaccine]],<ref name=":5">Liquid error: wrong number of arguments (given 1, expected 2)</ref> becoming the first country to approve this vaccine and the first country in the Western world to approve the use of any COVID‑19 vaccine.<ref name="mueller">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name=":6">Liquid error: wrong number of arguments (given 1, expected 2)</ref> As of 21 December, many countries and the European Union have authorized or approved the Pfizer-BioNTech COVID‑19 vaccine. [[Bahrain]] and the [[United Arab Emirates]] granted emergency marketing authorization for BBIBP-CorV, manufactured by [[China National Pharmaceutical Group#COVID%E2%80%9119 Vaccine: BBIBP-CorV|Sinopharm]].<ref name="bna">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="uae"></ref> On 11 December 2020, the United States [[Food and Drug Administration]] (FDA) granted an [[Emergency Use Authorization]] (EUA) for the Pfizer-BioNTech COVID‑19 vaccine.<ref name="thomas">Liquid error: wrong number of arguments (given 1, expected 2)</ref> A week later, they granted an EUA for [[mRNA-1273]], the Moderna vaccine.<ref name="CDC ACIP Moderna COVID-19 Vaccine">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="CNBC 20201219">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
== Planning and investment ==
Since early 2020, vaccine development has been expedited via unprecedented collaboration in the [[Pharmaceutical industry|multinational pharmaceutical industry]] and between governments.<ref name="thanh22">Liquid error: wrong number of arguments (given 1, expected 2)</ref> 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.<ref name="thanh22" /><ref name="thanh3">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
Commitment to first-in-human testing of a vaccine candidate represents a substantial capital cost for vaccine developers, estimated to be from million to million for a typical PhaseI trial program, but possibly as much as million.<ref name="gouglas2">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="dimasi2">Liquid error: wrong number of arguments (given 1, expected 2)</ref> For comparison, during the [[Western African Ebola virus epidemic|Ebola virus epidemic of 2013–16]], there were 37 vaccine candidates in urgent development with only one becoming a licensed vaccine at a total cost to confirm efficacy in PhaseII–III trials of about billion.<ref name="gouglas2" />
=== International organizations ===
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=== National governments ===
[[Government of Canada|Canada]] announced million in 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.<ref name="abedi">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="can-funding">Liquid error: wrong number of arguments (given 1, expected 2)</ref> A further investment of billion was added to support clinical trials and develop manufacturing and supply chains for vaccines.<ref name="can-research">Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 4May, the Canadian government committed million to the WHO's live streaming effort to raise billion for COVID‑19 vaccines and preparedness.<ref name="aiello">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
[[Government of China|China]] provided low-rate loans to a vaccine developer through its [[People's Bank of China|central bank]] and "quickly made land available for the company" to build production plants.<ref name="reuters">Liquid error: wrong number of arguments (given 1, expected 2)</ref> As of June 2020, six of the eleven COVID‑19 vaccine candidates in early-stage human testing were developed by Chinese organizations.<ref name="sanger">Liquid error: wrong number of arguments (given 1, expected 2)</ref> Three Chinese vaccine companies and research institutes are supported by the government for financing research, conducting clinical trials, and manufacturing the most promising vaccine candidates, prioritizing rapid evidence of efficacy over safety.<ref name="takada">Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 18 May, China had pledged billion to support overall efforts by the WHO for programs against COVID‑19.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 22 July, China announced plans to provide a US$1 billion loan to make its vaccine accessible for Latin America and the [[Caribbean]].<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 24 August, [[Premier of the People's Republic of China|Chinese Premier]] [[Li Keqiang]] announced it would provide Cambodia, Laos, Myanmar, Thailand, and Vietnam priority access to the vaccine once it was distributed.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
[[File:The_vaccine_development_process_typically_takes_10_to_15_years_under_a_traditional_timeline._Multiple_regulatory_pathways,_such_as_Emergency_Use_Authorization,_can_be_used_to_facilitate_bringing_a_vaccine_for_COVID-19_to_(49948301848).jpg|link=https://en.wikipedia.org/wiki/File:The_vaccine_development_process_typically_takes_10_to_15_years_under_a_traditional_timeline._Multiple_regulatory_pathways,_such_as_Emergency_Use_Authorization,_can_be_used_to_facilitate_bringing_a_vaccine_for_COVID-19_to_(49948301848).jpg|thumb|US [[Government Accountability Office]] diagram comparing a traditional vaccine development timeline to a possible expedited timeline]]
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.<ref name="morriss">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The vaccine development initiatives at the University of Oxford and [[Imperial College London|Imperial College of London]] were financed with million.<ref name="gartner">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="oxford">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In the United States, the [[Biomedical Advanced Research and Development Authority]] (BARDA), a federal agency funding disease-fighting technology, announced investments of nearly billion to support American COVID‑19 vaccine development and manufacture of the most promising candidates. On 16 April, BARDA made a million investment in vaccine developer [[Moderna]] and its partner, [[Johnson & Johnson]].<ref name="reuters" /><ref name="kuznia">Liquid error: wrong number of arguments (given 1, expected 2)</ref> BARDA has earmarked an additional billion for development. It will have a role in other programs for development of six to eight vaccine candidates destined for clinical study into 2021 by companies such as [[Sanofi Pasteur]] and [[Regeneron]].<ref name="kuznia" /><ref name="lee">Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 15 May, the government announced funding for a fast-track program called [[Operation Warp Speed]] to place multiple vaccine candidates into clinical trials by the fall of 2020 and manufacture 300million doses of a licensed vaccine by January 2021. The project's chief advisor is [[Moncef Slaoui]] and its chief operating officer is General [[Gustave F. Perna|Gustave Perna]].<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> In June, the Warp Speed team said it would work with seven companies developing vaccine candidates: [[Moderna]], [[Johnson & Johnson Pharmaceutical Research and Development|Johnson & Johnson]], [[Merck & Co.|Merck]], [[Pfizer]], the [[University of Oxford]] in collaboration with [[AstraZeneca]], and two others,<ref></ref> although Pfizer later stated that "all the investment for R&D was made by Pfizer at risk."<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== Pharmaceutical companies ===
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.<ref name="reuters" /><ref name="sanger" /> To combine financial and manufacturing capabilities for a pandemic [[Adjuvant|adjuvanted]] vaccine technology, GSK joined with [[Sanofi]] in an uncommon partnership of [[Multinational corporation|multinational companies]] to support accelerated vaccine development.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
By June 2020, tens of billions of dollars were invested by corporations, governments, international health organizations, and university research groups to develop dozens of vaccine candidates and prepare for global vaccination programs to immunize against COVID‑19 infection.<ref name="gates1">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="hbr">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="cbcr">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="ahmed">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The corporate investment and need to generate value for public shareholders raised concerns about a "market-based approach" in vaccine development, costly pricing of eventual licensed vaccines, preferred access for distribution first to affluent countries, and sparse or no distribution to where the pandemic is most aggressive, as predicted for densely-populated, impoverished countries unable to afford vaccinations.<ref name="gates1" /><ref name="sanger" /><ref name="cbcr" /> The collaboration of the University of Oxford with AstraZeneca (a global pharmaceutical company based in the UK) raised concerns about price and sharing of eventual profits from international vaccine sales, arising from whether the British government and university as public partners had commercialization rights.<ref name="ahmed" /> AstraZeneca stated that initial pricing of its vaccine would not include a [[profit margin]] for the company while the pandemic was still expanding.<ref name="ahmed" />
In early June, AstraZeneca made a US$750 million deal allowing CEPI and GAVI to manufacture and distribute 300 million doses if its Oxford vaccine candidate proved to be safe and effective, reportedly increasing the company's total production capacity to over 2 billion doses per year.<ref name="kyle">Liquid error: wrong number of arguments (given 1, expected 2)</ref> Commercialization of pandemic vaccines is a high-risk business venture, potentially losing billions of dollars in development and pre-market manufacturing costs if the candidate vaccines fail to be safe and effective.<ref name="gates1" /><ref name="reuters" /><ref name="sanger" /><ref name="hbr" /> Pfizer indicated it was not interested in a government partnership, considering it to be a "third party" slowing progress.<ref name="cohen6-4">Liquid error: wrong number of arguments (given 1, expected 2)</ref> Further, there are concerns that rapid-development programs–like Operation Warp Speed–are choosing candidates mainly for their manufacturing advantages rather than optimal safety and efficacy.<ref name="cohen6-4" />
== Development ==
CEPI classifies development stages for vaccines as "exploratory" (planning and designing a candidate, having no evaluation [[in vivo]]), "preclinical" (in vivo evaluation with preparation for manufacturing a compound to test in humans), or [[Phases of clinical research#Phase I|initiation of PhaseI safety studies in healthy people]].<ref name="thanh22" /> Some 321 total vaccine candidates were in development as either confirmed projects in clinical trials or in early-stage "exploratory" or "preclinical" development, as of September.<ref name="thanh22" />
=== Early development ===
[[File:Scientist_examines_COVID-19_vaccine_agar_plate.jpg|link=https://en.wikipedia.org/wiki/File:Scientist_examines_COVID-19_vaccine_agar_plate.jpg|thumb|NIAID (NIH) scientist researching COVID‑19 vaccine examines agar plate. (30 January 2020)]]
After a coronavirus was isolated in December 2019,<ref name="who-time">Liquid error: wrong number of arguments (given 1, expected 2)</ref> its [[Nucleic acid sequence|genetic sequence]] was published on 11 January 2020, triggering an urgent international response to prepare for an outbreak and hasten development of a preventive vaccine.<ref name="thanh3" /><ref name="gates1" /><ref name="Fauci">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In February 2020, the 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.<ref name=":0">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The rapidly growing infection rate of COVID‑19 worldwide during early 2020 stimulated international alliances and government efforts to urgently organize resources to make multiple vaccines on shortened timelines,<ref name="who-accel">Liquid error: wrong number of arguments (given 1, expected 2)billion. This estimate includes Phase1 clinical trials of eight vaccine candidates, progression of up to six candidates through Phase2 and3 trials, completion of regulatory and quality requirements for at least three vaccines, and enhancing global manufacturing capacity for three vaccines.|doi-access=free}}</ref> with four vaccine candidates entering human evaluation in March (see the table of [[COVID-19 vaccine#Clinical trials started in 2020|clinical trials started in 2020]], below).<ref name="thanh3" /><ref name="yamey">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In April 2020, the WHO estimated a total cost of billion to develop a suite of three or more vaccines having different technologies and distribution.<ref name="who-accel" />
By April 2020, "almost 80 companies and institutes in 19 countries" were working on this virtual gold rush.<ref name="cssa">Liquid error: wrong number of arguments (given 1, expected 2)</ref> Also in April, CEPI estimated that as many as six of the vaccine candidates against COVID‑19 should be chosen by international coalitions for development through PhaseII–III trials, and three should be streamlined through regulatory and quality assurance for eventual licensing at a total cost of at least billion.<ref name="thanh22" /><ref name="yamey" /><ref name="gates2">Liquid error: wrong number of arguments (given 1, expected 2)</ref> Another analysis estimates ten candidates will need simultaneous initial development, before a select few are chosen for the final path to licensing.<ref name="gates2" />
In July 2020, Anglo-American intelligence and security organisations of the respective governments and armed forces, as the UK's [[National Cyber Security Centre (United Kingdom)|National Cyber Security Centre]], together with the Canadian [[Communications Security Establishment]], the United States Department for Homeland Security [[Cybersecurity and Infrastructure Security Agency|Cybersecurity Infrastructure Security Agency]], and the US [[National Security Agency]] (NSA) alleged that Russian state-backed hackers may have been trying to steal COVID‑19 treatment and vaccine research from academic and pharmaceutical institutions in other countries; Russia has denied it.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== Preclinical research ===
[[File:COVID-19_vaccine_in_NIAID_lab_freezer.jpg|link=https://en.wikipedia.org/wiki/File:COVID-19_vaccine_in_NIAID_lab_freezer.jpg|thumb|COVID‑19 vaccine research samples in [[NIAID]] lab freezer. (30 January 2020)]]
In April 2020, the WHO issued a statement representing dozens of vaccine scientists around the world, pledging collaboration to speed development of a vaccine against COVID‑19.<ref name="who-scientists">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The WHO coalition is encouraging international cooperation between organizations developing vaccine candidates, national regulatory and policy agencies, financial contributors, public health associations, and governments, for eventual manufacturing of a successful vaccine in quantities sufficient to supply all affected regions, particularly low-resource countries.<ref name="thanh3" />
Industry analysis of past vaccine development shows failure rates of 84–90%.<ref name="thanh3" /><ref name="bio">Liquid error: wrong number of arguments (given 1, expected 2)</ref> 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.<ref name="thanh3" />
To assess the potential for vaccine efficacy, unprecedented computer simulations and new COVID‑19-specific animal models are being developed multinationally during 2020, but these methods remain untested by unknown characteristics of the COVID‑19 virus.<ref name="thanh3" /> Of the confirmed active vaccine candidates, about 70% are being developed by private companies, with the remaining projects under development by academic, government coalitions, and health organizations.<ref name="thanh22" />
Most of the vaccine developers are small firms or university research teams with little experience in successful vaccine design and limited capacity for advanced clinical trial costs and manufacturing without partnership by multinational pharmaceutical companies.<ref name="thanh22" /><ref name="thanh3" />
Historically, the probability of success for an infectious disease vaccine candidate to pass preclinical barriers and reach PhaseI of human testing is 41–57%.<ref name="gouglas2" />
=== Challenges ===
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.<ref name="diamond">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="thanh3" /><ref name="Thorp">Liquid error: wrong number of arguments (given 1, expected 2)</ref> One study found that between 2006 and 2015, the success rate of obtaining approval from PhaseI to successful PhaseIII trials was 16.2% for vaccines,<ref name="bio" /> and CEPI indicates a potential success rate of only 10% for vaccine candidates in 2020 development.<ref name="thanh3" />
Research at universities is obstructed by [[Social distancing|physical distancing]] and closing of laboratories.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
==== Biosafety ====
Early research to assess vaccine efficacy using COVID‑19-specific animal models, such as [[ACE2]]-[[transgenic]] mice, other laboratory animals, and non-human primates, indicates a need for [[biosafety]]-level3 containment measures for handling live viruses, and international coordination to ensure standardized safety procedures.<ref name="diamond" /><ref name="thanh3" />
==== Antibody-dependent enhancement ====
Although the quality and quantity of [[antibody]] production by a potential vaccine is intended to neutralize the COVID‑19 infection, a vaccine may have an unintended opposite effect by causing [[Antibody-dependent enhancement|antibody-dependent disease enhancement]] (ADE), which increases the virus attachment to its target cells and might trigger a [[cytokine storm]] if a vaccinated person is later attacked by the virus.<ref name="diamond" /><ref name="iwasaki">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The vaccine technology platform (for example, [[viral vector]] vaccine, [[Severe acute respiratory syndrome-related coronavirus#Morphology|spike (S) protein]] vaccine or [[protein subunit]] vaccine), vaccine dose, timing of repeat vaccinations for the possible recurrence of COVID‑19 infection, and elderly age are factors determining the risk and extent of ADE.<ref name="diamond" /><ref name="iwasaki" /> The antibody response to a vaccine is a variable of vaccine technologies in development, including whether the vaccine has precision in its mechanism,<ref name="diamond" /> and choice of the route for how it is given ([[Intramuscular injection|intramuscular]], [[Intradermal injection|intradermal]], oral, or nasal).<ref name="iwasaki" />
== Trials ==
[[File:Covid_vaccine_clinical_trial,_Padjajaran_University_(cropped).jpg|link=https://en.wikipedia.org/wiki/File:Covid_vaccine_clinical_trial,_Padjajaran_University_(cropped).jpg|thumb|Volunteer receives CoronaVac injection during Phase III trial by Sinovac in Indonesia.]]
[[File:BNT162b2_vaccine_efficacy_data.png|link=https://en.wikipedia.org/wiki/File:BNT162b2_vaccine_efficacy_data.png|thumb|Cumulative incidence curves for symptomatic COVID‑19 infections after the first dose of the Pfizer-BioNTech vaccine (tozinameran) or placebo in a double-blind clinical trial. (red: placebo; blue: tozinameran)<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>]]
In April 2020, the WHO published an "R&D Blueprint (for the) novel Coronavirus" (Blueprint). The Blueprint 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 Blueprint listed a ''Global Target Product Profile'' (TPP) for COVID‑19, identifying favorable attributes of safe and effective vaccines under two broad categories: "vaccines for the long-term protection of people at higher risk of COVID‑19, such as healthcare workers", and other vaccines to provide rapid-response immunity for new outbreaks.<ref name="who-accel" /> The international TPP team was formed to 1) assess the development of the most promising candidate vaccines; 2) map candidate vaccines and their clinical trial worldwide, publishing a frequently-updated "landscape" of vaccines in development;<ref name="who-tracker">Liquid error: wrong number of arguments (given 1, expected 2)</ref> 3) rapidly evaluate and screen for the most promising candidate vaccines simultaneously before they are tested in humans; and 4) design and coordinate a multiple-site, international [[randomized controlled trial]]the "Solidarity trial" for vaccines<ref name="who-accel" /><ref name="solidarity-vacc"></ref>to enable simultaneous evaluation of the benefits and risks of different vaccine candidates under clinical trials in countries where there are high rates of COVID‑19 disease, ensuring fast interpretation and sharing of results around the world.<ref name="who-accel" /> 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.<ref name="who-accel" />
PhaseI trials test primarily for safety and preliminary dosing in a few dozen healthy subjects, while PhaseII trialsfollowing success in PhaseIevaluate [[immunogenicity]], dose levels (efficacy based on [[Biomarker|biomarkers]]) and adverse effects of the candidate vaccine, typically in hundreds of people.<ref name="Vaccines.gov">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="fda-ddp">Liquid error: wrong number of arguments (given 1, expected 2)</ref> A PhaseI–II trial consists of preliminary safety and immunogenicity testing, is typically randomized, placebo-controlled, while determining more precise, effective doses.<ref name="fda-ddp" /> 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 effect|adverse effects]] at the optimal dose.<ref name="Vaccines.gov" /><ref name="fda-ddp" /> Definition of vaccine safety, efficacy, and [[Clinical endpoint|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.<ref name="cohen6-19">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="cdc-eff">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== Enrollment of participants ===
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 indication|moving target]]" of changing transmission rate across and within countries, forcing companies to compete for trial participants.<ref name="cohen6-19" /> As an example in June, the Chinese vaccine developer Sinovac formed alliances in [[Malaysia]], Canada, the UK, and Brazil among its plans to recruit trial participants and manufacture enough vaccine doses for a possible PhaseIII study in Brazil where COVID‑19 transmission was accelerating during June.<ref name="cohen6-19" /> As the COVID‑19 pandemic within China became more isolated and controlled, Chinese vaccine developers sought international relationships to conduct advanced human studies in several countries, creating competition for trial participants with other manufacturers and the international Solidarity trial organized by the WHO.<ref name="cohen6-19" /> In addition to competition over recruiting participants, clinical trial organizers may encounter people unwilling to be vaccinated due to [[vaccine hesitancy]]<ref name="dube">Liquid error: wrong number of arguments (given 1, expected 2)</ref> or disbelieving the science of the vaccine technology and its ability to prevent infection.<ref name="howard-cnn">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
Having an insufficient number of skilled team members to administer vaccinations may hinder clinical trials that must overcome risks for trial failure, such as recruiting participants in rural or low-density geographic regions, and variations of age, race, ethnicity, or underlying medical conditions.<ref name="cohen6-19" /><ref name="winter">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== Adaptive design for the Solidarity trial ===
A clinical trial design in progress may be modified as an [[Adaptive design (medicine)|"adaptive design"]] if accumulating data in the trial provide early insights about positive or negative efficacy of the treatment.<ref name="pallmann">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="fda-adaptive">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The WHO Solidarity trial of multiple vaccines in clinical studies during 2020, will apply adaptive design to rapidly alter trial parameters across all study sites as results emerge.<ref name="solidarity-vacc" /> Candidate vaccines may be added to the Solidarity trial as they become available if priority criteria are met, while vaccine candidates showing poor evidence of safety or efficacy compared to placebo or other vaccines will be dropped from the international trial.<ref name="solidarity-vacc" />
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.<ref name="solidarity-vacc" /><ref name="pallmann" />
=== Proposed challenge studies ===
[[Human challenge study|Challenge studies]] are a type of clinical trial involving the intentional exposure of the test subject to the condition tested, an approach that can significantly accelerate vaccine development.<ref name="lamb">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="eyal">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="callaway">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="cohen">Liquid error: wrong number of arguments (given 1, expected 2)</ref> Human challenge studies may be ethically controversial because they involve exposing test subjects to dangers beyond those posed by potential [[Side effect|side effects]] of the substance being tested.<ref name="eyal" /><ref name="callaway" /> Challenge studies have been used for diseases less deadly than COVID‑19 infection, such as common influenza, [[typhoid fever]], [[cholera]], and [[malaria]].<ref name="callaway" /><ref name="cohen" /> The World Health Organization has developed a guidance document with criteria for conducting COVID‑19 challenge studies in healthy people, including scientific and ethical evaluation, public consultation and coordination, selection and [[informed consent]] of the participants, and monitoring by independent experts.<ref name="who-challenge">Liquid error: wrong number of arguments (given 1, expected 2)</ref> Beginning in January 2021, dozens of young adult volunteers will be deliberately infected with COVID‑19 in a challenge trial conducted in a London hospital under management by the British government COVID‑19 Vaccine Taskforce.<ref name="call-challenge" /> Once an infection dose of COVID‑19 is identified, two or more of the candidate COVID‑19 vaccines will be tested for effectiveness in preventing infection.<ref name="call-challenge" />
== Authorizations and licensure ==
At the beginning of the COVID‑19 pandemic in early 2020, the WHO issued a guideline as an Emergency Use Listing of new vaccines, a process derived from the 2013–16 [[Western African Ebola virus epidemic|Ebola epidemic]].<ref name="who-eul">Liquid error: wrong number of arguments (given 1, expected 2)</ref> It required that a vaccine candidate developed for a life-threatening emergency be manufactured using GMP and that it complete development according to WHO prequalification procedures.<ref name="who-eul" />
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. In the UK and the EU, companies may use a "rolling review process", supplying data as they become available during Phase III trials, rather than developing the full documentation over months or years at the end of clinical research, as is typical. This rolling process allows the [[Medicines and Healthcare products Regulatory Agency|UK's regulator (MHRA)]] and the European Committee for Medicinal Products for Human Use to evaluate clinical data in real time, enabling a promising vaccine candidate to be approved on a rapid timeline by both the UK's MHRA and the [[European Medicines Agency]] (EMA).<ref name="ema-eau"></ref> A rolling review process for the Moderna vaccine candidate was initiated in October by [[Health Canada]] and the EMA,<ref name="byrne10-19">Liquid error: wrong number of arguments (given 1, expected 2)</ref> and in November in Canada for the Pfizer-BioNTech candidate.<ref name="dangerfield">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In the United States, an [[Emergency Use Authorization]] (EUA) is "a mechanism to facilitate the availability and use of medical countermeasures, including vaccines, during public health emergencies, such as the current COVID‑19 pandemic."<ref name="fda-eua">Liquid error: wrong number of arguments (given 1, expected 2) </ref> Once an EUA is issued by the FDA, the vaccine developer is expected to continue the Phase III clinical trial to finalize safety and efficacy data, leading to application for licensure (approval) in the United States.<ref name="fda-eua" /> In mid-2020, concerns that the FDA might grant a vaccine EUA before full evidence from a Phase III clinical trial was available raised broad concerns about the potential for lowered standards in the face of political pressure.<ref name="malik"></ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="hoffman">Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 8 September 2020, nine leading pharmaceutical companies involved in COVID‑19 vaccine research signed a letter, pledging that they would submit their vaccines for emergency use authorization only after Phase III trials had demonstrated safety and efficacy.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== Early authorizations in China and Russia ===
On 24 June 2020, China approved the CanSino vaccine for limited use in the military and two inactivated virus vaccines for emergency use in high-risk occupations.<ref name=":1" /> On 11 August 2020, Russia announced the approval of its Sputnik V vaccine for emergency use, though one month later only small amounts of the vaccine had been distributed for use outside of the phase 3 trial.<ref name=":2" /> In September, the [[United Arab Emirates]] approved emergency use of [[China National Pharmaceutical Group|Sinopharm]]'s vaccine for healthcare workers,<ref></ref> followed by similar emergency use approval from [[Bahrain]] in November.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== First authorizations of RNA vaccines ===
[[File:Pfizer-BioNTech_COVID-19_vaccine_(2020)_G.jpg|link=https://en.wikipedia.org/wiki/File:Pfizer-BioNTech_COVID-19_vaccine_(2020)_G.jpg|thumb|Pfizer-BioNTech COVID-19 vaccine.]]
The Pfizer-BioNTech partnership submitted an EUA request to the FDA for the mRNA vaccine BNT162b2 (active ingredient [[tozinameran]]) on 20 November 2020.<ref name=":3" /><ref name=":4" /> On 2 December 2020, the United Kingdom's [[Medicines and Healthcare products Regulatory Agency]] (MHRA) gave temporary regulatory approval for the [[Pfizer-BioNTech COVID‑19 vaccine|Pfizer–BioNTech vaccine]],<ref name=":5" /> becoming the first country to approve this vaccine and the first country in the Western world to approve the use of any COVID‑19 vaccine.<ref name="mueller" /><ref name=":6" /> On 8 December 2020, 90-year-old Margaret Keenan received the vaccine at [[University Hospital Coventry]], becoming the first person known to be vaccinated outside of a trial,<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> as the [[COVID‑19 vaccination programme in the United Kingdom|UK's vaccination programme]] began.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> However, other vaccines had been given earlier in Russia.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 11 December 2020, the US [[Food and Drug Administration]] (FDA) granted an Emergency Use Authorization (EUA) for the Pfizer-BioNTech vaccine.<ref name="thomas" /><ref name="pmid 33332292">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The vaccine has subsequently been approved for use by a number of national health authorities.Liquid error: wrong number of arguments (given 1, expected 2) On 19 December 2020, the [[Swissmedic|Swiss Agency for Therapeutic Products (Swissmedic)]] approved the Pfizer-BioNTech vaccine for regular use, two months after receiving the application. This was the first authorization by a [[stringent regulatory authority]] under a standard procedure for any COVID‑19 vaccine.<ref name="Swiss authorization">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 23 December, a 90-year-old [[Lucerne]] resident became the first person to receive the vaccine in continental Europe.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
As of 21 December, many countries and the European Union have authorized or approved the Pfizer-BioNTech COVID‑19 vaccine. [[Bahrain]] and the [[United Arab Emirates]] granted emergency marketing authorization for BBIBP-CorV, manufactured by [[China National Pharmaceutical Group#COVID%E2%80%9119 Vaccine: BBIBP-CorV|Sinopharm]].<ref name="bna" /><ref name="uae" /> In the United Kingdom, 138,000 people had received the Pfizer-BioNTech COVID‑19 vaccine Cominarty by 16 December, during the first week of the [[COVID‑19 vaccination programme in the United Kingdom|UK vaccination programme]].<ref name="graun-138">Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 11 December 2020, the United States [[Food and Drug Administration]] (FDA) granted an [[Emergency Use Authorization]] (EUA) for the Pfizer-BioNTech COVID‑19 vaccine.<ref name="thomas" /> A week later, they granted an EUA for [[mRNA-1273]], the Moderna vaccine.<ref name="CDC ACIP Moderna COVID-19 Vaccine" /><ref name="CNBC 20201219" /> Vaccine manufacturers are awaiting full approvals to name their vaccines.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
Moderna submitted a request for an EUA for [[mRNA-1273]] to the FDA on 30 November 2020.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 18 December 2020, the FDA granted an EUA for the Moderna vaccine.<ref name="CDC ACIP Moderna COVID-19 Vaccine" /><ref name="CNBC 20201219" />
=== United Kingdom ===
The [[Medicines and Healthcare products Regulatory Agency|UK's regulator (MHRA)]] gave the first approval to the [[AZD1222|Oxford/AstraZeneca]] vaccine on 30 December 2020, as their second vaccine to enter the [[COVID‑19 vaccination programme in the United Kingdom|national rollout]].<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== Australia ===
In October 2020, the Australian [[Therapeutic Goods Administration]] (TGA) granted provisional determinations to AstraZeneca Pty Ltd in relation to its COVID‑19 vaccine, ChAdOx1-S [recombinant] and to Pfizer Australia Pty Ltd in relation to its COVID‑19 vaccine, [[Tozinameran|BNT162b2]] [mRNA].<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> Janssen Cilag Pty Ltd was granted a provisional determination in relation to its COVID‑19 vaccine, Ad26.COV2.S, in November 2020.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== European Union ===
In October 2020, the [[Committee for Medicinal Products for Human Use]] (CHMP) started 'rolling reviews' of the vaccines known as ''COVID‑19 Vaccine AstraZeneca'' (ChAdOx1-SARS-CoV-2) and ''Pfizer-BioNTech COVID‑19 Vaccine'' ([[Tozinameran|BNT162b2]]).<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> The EMA released an update on the status of its rolling review of the COVID‑19 Vaccine AstraZeneca in December 2020, after the UK granted a temporary authorization of supply for the vaccine.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In November 2020, the EMA published a safety monitoring plan and guidance on risk management planning (RMP) for COVID‑19 vaccines.<ref name="EMA PR 20201113">Liquid error: wrong number of arguments (given 1, expected 2) Text was copied from this source which is European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> The plan outlines how relevant new information emerging after the authorization and uptake of COVID‑19 vaccines in the pandemic situation will be collected and promptly reviewed.<ref name="EMA PR 20201113" /> All RMPs for COVID‑19 vaccines will be published on the EMA's website.<ref name="EMA PR 20201113" /> The EMA published guidance for developers of potential COVID‑19 vaccines on the clinical evidence to include in marketing authorization applications.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In November 2020, the CHMP started a rolling review of the Moderna vaccine for COVID‑19 known as mRNA-1273.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In December 2020, the EMA received application for conditional marketing authorizations (CMA) for the mRNA vaccines ''BNT162b2'' and ''mRNA1273'' (''Moderna Covid‑19 vaccine'').<ref name="EMA mRNA1273 application">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="EMA BNT162b2 application">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The assessments of the vaccines are scheduled to proceed under accelerated timelines with the possibility of opinions issued within weeks.<ref name="EMA mRNA1273 application" /><ref name="EMA BNT162b2 application" /><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In December 2020, the CHMP started a rolling review of the Ad26.COV2.S COVID‑19 vaccine from Janssen-Cilag International N.V.<ref name="EU Ad26.COV2.S rolling review">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
On 21 December 2020, the CHMP recommended granting a conditional marketing authorization for the Pfizer-BioNTech COVID‑19 vaccine, Comirnaty (active ingredient tozinameran), developed by BioNTech and Pfizer.<ref name="EU PR 20201221">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="Comirnaty: Pending EC decision">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The recommendation was accepted by the [[European Commission]] the same day.<ref name="EU PR 20201221" /><ref name="EU statement"></ref>
In January 2021, the EMA received an application for conditional marketing authorization (CMA) for the COVID‑19 vaccine known as ''[[AZD1222|COVID‑19 Vaccine AstraZeneca]]'', developed by AstraZeneca and Oxford University.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
== References ==
[[Category:COVID-19 vaccines| ]]
[[Category:Medical research]]
[[Category:Medical responses to the COVID-19 pandemic]]
After a coronavirus was isolated in December 2019,<ref name="who-time" /> its [[Nucleic acid sequence|genetic sequence]] was published on 11 January 2020, triggering an urgent international response to prepare for an outbreak and hasten development of a preventive vaccine.<ref name="thanh3" /><ref name="gates1" /><ref name="Fauci" /> Since early 2020, [[COVID-19 vaccine]] development has been expedited via unprecedented collaboration in the [[Pharmaceutical industry|multinational pharmaceutical industry]] and between governments.<ref name="thanh22" /> By June 2020, tens of billions of dollars were invested by corporations, governments, international health organizations, and university research groups to develop dozens of vaccine candidates and prepare for global vaccination programs to immunize against COVID‑19 infection.<ref name="gates1" /><ref name="hbr" /><ref name="cbcr" /><ref name="ahmed" /> 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.<ref name="thanh22" /><ref name="thanh3" />
In February 2020, the 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.<ref name=":0" /> The rapidly growing infection rate of COVID‑19 worldwide during early 2020 stimulated international alliances and government efforts to urgently organize resources to make multiple vaccines on shortened timelines,<ref name="who-accel" /> with four vaccine candidates entering human evaluation in March (see the table of [[COVID-19 vaccine#Clinical trials started in 2020|clinical trials started in 2020]], below).<ref name="thanh3" /><ref name="yamey" />
On 24 June 2020, China approved the CanSino vaccine for limited use in the military and two inactivated virus vaccines for emergency use in high-risk occupations.<ref name=":1">Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 11 August 2020, Russia announced the approval of its Sputnik V vaccine for emergency use, though one month later only small amounts of the vaccine had been distributed for use outside of the phase 3 trial.<ref name=":2">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
The Pfizer-BioNTech partnership submitted an EUA request to the FDA for the mRNA vaccine BNT162b2 (active ingredient [[tozinameran]]) on 20 November 2020.<ref name=":3">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name=":4">Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 2 December 2020, the United Kingdom's [[Medicines and Healthcare products Regulatory Agency]] (MHRA) gave temporary regulatory approval for the [[Pfizer-BioNTech COVID‑19 vaccine|Pfizer–BioNTech vaccine]],<ref name=":5">Liquid error: wrong number of arguments (given 1, expected 2)</ref> becoming the first country to approve this vaccine and the first country in the Western world to approve the use of any COVID‑19 vaccine.<ref name="mueller">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name=":6">Liquid error: wrong number of arguments (given 1, expected 2)</ref> As of 21 December, many countries and the European Union have authorized or approved the Pfizer-BioNTech COVID‑19 vaccine. [[Bahrain]] and the [[United Arab Emirates]] granted emergency marketing authorization for BBIBP-CorV, manufactured by [[China National Pharmaceutical Group#COVID%E2%80%9119 Vaccine: BBIBP-CorV|Sinopharm]].<ref name="bna">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="uae"></ref> On 11 December 2020, the United States [[Food and Drug Administration]] (FDA) granted an [[Emergency Use Authorization]] (EUA) for the Pfizer-BioNTech COVID‑19 vaccine.<ref name="thomas">Liquid error: wrong number of arguments (given 1, expected 2)</ref> A week later, they granted an EUA for [[mRNA-1273]], the Moderna vaccine.<ref name="CDC ACIP Moderna COVID-19 Vaccine">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="CNBC 20201219">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
== Planning and investment ==
Since early 2020, vaccine development has been expedited via unprecedented collaboration in the [[Pharmaceutical industry|multinational pharmaceutical industry]] and between governments.<ref name="thanh22">Liquid error: wrong number of arguments (given 1, expected 2)</ref> 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.<ref name="thanh22" /><ref name="thanh3">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
Commitment to first-in-human testing of a vaccine candidate represents a substantial capital cost for vaccine developers, estimated to be from million to million for a typical PhaseI trial program, but possibly as much as million.<ref name="gouglas2">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="dimasi2">Liquid error: wrong number of arguments (given 1, expected 2)</ref> For comparison, during the [[Western African Ebola virus epidemic|Ebola virus epidemic of 2013–16]], there were 37 vaccine candidates in urgent development with only one becoming a licensed vaccine at a total cost to confirm efficacy in PhaseII–III trials of about billion.<ref name="gouglas2" />
=== International organizations ===
==== Access to COVID‑19 Tools (ACT) Accelerator ====<!--CONTENT IN THIS SECTION IS TRANSCLUDED FROM Access to COVID-19 Tools Accelerator. TO EDIT, PLEASE NAVIGATE TO THAT TOPIC-->
=== National governments ===
[[Government of Canada|Canada]] announced million in 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.<ref name="abedi">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="can-funding">Liquid error: wrong number of arguments (given 1, expected 2)</ref> A further investment of billion was added to support clinical trials and develop manufacturing and supply chains for vaccines.<ref name="can-research">Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 4May, the Canadian government committed million to the WHO's live streaming effort to raise billion for COVID‑19 vaccines and preparedness.<ref name="aiello">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
[[Government of China|China]] provided low-rate loans to a vaccine developer through its [[People's Bank of China|central bank]] and "quickly made land available for the company" to build production plants.<ref name="reuters">Liquid error: wrong number of arguments (given 1, expected 2)</ref> As of June 2020, six of the eleven COVID‑19 vaccine candidates in early-stage human testing were developed by Chinese organizations.<ref name="sanger">Liquid error: wrong number of arguments (given 1, expected 2)</ref> Three Chinese vaccine companies and research institutes are supported by the government for financing research, conducting clinical trials, and manufacturing the most promising vaccine candidates, prioritizing rapid evidence of efficacy over safety.<ref name="takada">Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 18 May, China had pledged billion to support overall efforts by the WHO for programs against COVID‑19.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 22 July, China announced plans to provide a US$1 billion loan to make its vaccine accessible for Latin America and the [[Caribbean]].<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 24 August, [[Premier of the People's Republic of China|Chinese Premier]] [[Li Keqiang]] announced it would provide Cambodia, Laos, Myanmar, Thailand, and Vietnam priority access to the vaccine once it was distributed.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
[[File:The_vaccine_development_process_typically_takes_10_to_15_years_under_a_traditional_timeline._Multiple_regulatory_pathways,_such_as_Emergency_Use_Authorization,_can_be_used_to_facilitate_bringing_a_vaccine_for_COVID-19_to_(49948301848).jpg|link=https://en.wikipedia.org/wiki/File:The_vaccine_development_process_typically_takes_10_to_15_years_under_a_traditional_timeline._Multiple_regulatory_pathways,_such_as_Emergency_Use_Authorization,_can_be_used_to_facilitate_bringing_a_vaccine_for_COVID-19_to_(49948301848).jpg|thumb|US [[Government Accountability Office]] diagram comparing a traditional vaccine development timeline to a possible expedited timeline]]
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.<ref name="morriss">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The vaccine development initiatives at the University of Oxford and [[Imperial College London|Imperial College of London]] were financed with million.<ref name="gartner">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="oxford">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In the United States, the [[Biomedical Advanced Research and Development Authority]] (BARDA), a federal agency funding disease-fighting technology, announced investments of nearly billion to support American COVID‑19 vaccine development and manufacture of the most promising candidates. On 16 April, BARDA made a million investment in vaccine developer [[Moderna]] and its partner, [[Johnson & Johnson]].<ref name="reuters" /><ref name="kuznia">Liquid error: wrong number of arguments (given 1, expected 2)</ref> BARDA has earmarked an additional billion for development. It will have a role in other programs for development of six to eight vaccine candidates destined for clinical study into 2021 by companies such as [[Sanofi Pasteur]] and [[Regeneron]].<ref name="kuznia" /><ref name="lee">Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 15 May, the government announced funding for a fast-track program called [[Operation Warp Speed]] to place multiple vaccine candidates into clinical trials by the fall of 2020 and manufacture 300million doses of a licensed vaccine by January 2021. The project's chief advisor is [[Moncef Slaoui]] and its chief operating officer is General [[Gustave F. Perna|Gustave Perna]].<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> In June, the Warp Speed team said it would work with seven companies developing vaccine candidates: [[Moderna]], [[Johnson & Johnson Pharmaceutical Research and Development|Johnson & Johnson]], [[Merck & Co.|Merck]], [[Pfizer]], the [[University of Oxford]] in collaboration with [[AstraZeneca]], and two others,<ref></ref> although Pfizer later stated that "all the investment for R&D was made by Pfizer at risk."<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== Pharmaceutical companies ===
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.<ref name="reuters" /><ref name="sanger" /> To combine financial and manufacturing capabilities for a pandemic [[Adjuvant|adjuvanted]] vaccine technology, GSK joined with [[Sanofi]] in an uncommon partnership of [[Multinational corporation|multinational companies]] to support accelerated vaccine development.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
By June 2020, tens of billions of dollars were invested by corporations, governments, international health organizations, and university research groups to develop dozens of vaccine candidates and prepare for global vaccination programs to immunize against COVID‑19 infection.<ref name="gates1">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="hbr">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="cbcr">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="ahmed">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The corporate investment and need to generate value for public shareholders raised concerns about a "market-based approach" in vaccine development, costly pricing of eventual licensed vaccines, preferred access for distribution first to affluent countries, and sparse or no distribution to where the pandemic is most aggressive, as predicted for densely-populated, impoverished countries unable to afford vaccinations.<ref name="gates1" /><ref name="sanger" /><ref name="cbcr" /> The collaboration of the University of Oxford with AstraZeneca (a global pharmaceutical company based in the UK) raised concerns about price and sharing of eventual profits from international vaccine sales, arising from whether the British government and university as public partners had commercialization rights.<ref name="ahmed" /> AstraZeneca stated that initial pricing of its vaccine would not include a [[profit margin]] for the company while the pandemic was still expanding.<ref name="ahmed" />
In early June, AstraZeneca made a US$750 million deal allowing CEPI and GAVI to manufacture and distribute 300 million doses if its Oxford vaccine candidate proved to be safe and effective, reportedly increasing the company's total production capacity to over 2 billion doses per year.<ref name="kyle">Liquid error: wrong number of arguments (given 1, expected 2)</ref> Commercialization of pandemic vaccines is a high-risk business venture, potentially losing billions of dollars in development and pre-market manufacturing costs if the candidate vaccines fail to be safe and effective.<ref name="gates1" /><ref name="reuters" /><ref name="sanger" /><ref name="hbr" /> Pfizer indicated it was not interested in a government partnership, considering it to be a "third party" slowing progress.<ref name="cohen6-4">Liquid error: wrong number of arguments (given 1, expected 2)</ref> Further, there are concerns that rapid-development programs–like Operation Warp Speed–are choosing candidates mainly for their manufacturing advantages rather than optimal safety and efficacy.<ref name="cohen6-4" />
== Development ==
CEPI classifies development stages for vaccines as "exploratory" (planning and designing a candidate, having no evaluation [[in vivo]]), "preclinical" (in vivo evaluation with preparation for manufacturing a compound to test in humans), or [[Phases of clinical research#Phase I|initiation of PhaseI safety studies in healthy people]].<ref name="thanh22" /> Some 321 total vaccine candidates were in development as either confirmed projects in clinical trials or in early-stage "exploratory" or "preclinical" development, as of September.<ref name="thanh22" />
=== Early development ===
[[File:Scientist_examines_COVID-19_vaccine_agar_plate.jpg|link=https://en.wikipedia.org/wiki/File:Scientist_examines_COVID-19_vaccine_agar_plate.jpg|thumb|NIAID (NIH) scientist researching COVID‑19 vaccine examines agar plate. (30 January 2020)]]
After a coronavirus was isolated in December 2019,<ref name="who-time">Liquid error: wrong number of arguments (given 1, expected 2)</ref> its [[Nucleic acid sequence|genetic sequence]] was published on 11 January 2020, triggering an urgent international response to prepare for an outbreak and hasten development of a preventive vaccine.<ref name="thanh3" /><ref name="gates1" /><ref name="Fauci">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In February 2020, the 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.<ref name=":0">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The rapidly growing infection rate of COVID‑19 worldwide during early 2020 stimulated international alliances and government efforts to urgently organize resources to make multiple vaccines on shortened timelines,<ref name="who-accel">Liquid error: wrong number of arguments (given 1, expected 2)billion. This estimate includes Phase1 clinical trials of eight vaccine candidates, progression of up to six candidates through Phase2 and3 trials, completion of regulatory and quality requirements for at least three vaccines, and enhancing global manufacturing capacity for three vaccines.|doi-access=free}}</ref> with four vaccine candidates entering human evaluation in March (see the table of [[COVID-19 vaccine#Clinical trials started in 2020|clinical trials started in 2020]], below).<ref name="thanh3" /><ref name="yamey">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In April 2020, the WHO estimated a total cost of billion to develop a suite of three or more vaccines having different technologies and distribution.<ref name="who-accel" />
By April 2020, "almost 80 companies and institutes in 19 countries" were working on this virtual gold rush.<ref name="cssa">Liquid error: wrong number of arguments (given 1, expected 2)</ref> Also in April, CEPI estimated that as many as six of the vaccine candidates against COVID‑19 should be chosen by international coalitions for development through PhaseII–III trials, and three should be streamlined through regulatory and quality assurance for eventual licensing at a total cost of at least billion.<ref name="thanh22" /><ref name="yamey" /><ref name="gates2">Liquid error: wrong number of arguments (given 1, expected 2)</ref> Another analysis estimates ten candidates will need simultaneous initial development, before a select few are chosen for the final path to licensing.<ref name="gates2" />
In July 2020, Anglo-American intelligence and security organisations of the respective governments and armed forces, as the UK's [[National Cyber Security Centre (United Kingdom)|National Cyber Security Centre]], together with the Canadian [[Communications Security Establishment]], the United States Department for Homeland Security [[Cybersecurity and Infrastructure Security Agency|Cybersecurity Infrastructure Security Agency]], and the US [[National Security Agency]] (NSA) alleged that Russian state-backed hackers may have been trying to steal COVID‑19 treatment and vaccine research from academic and pharmaceutical institutions in other countries; Russia has denied it.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== Preclinical research ===
[[File:COVID-19_vaccine_in_NIAID_lab_freezer.jpg|link=https://en.wikipedia.org/wiki/File:COVID-19_vaccine_in_NIAID_lab_freezer.jpg|thumb|COVID‑19 vaccine research samples in [[NIAID]] lab freezer. (30 January 2020)]]
In April 2020, the WHO issued a statement representing dozens of vaccine scientists around the world, pledging collaboration to speed development of a vaccine against COVID‑19.<ref name="who-scientists">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The WHO coalition is encouraging international cooperation between organizations developing vaccine candidates, national regulatory and policy agencies, financial contributors, public health associations, and governments, for eventual manufacturing of a successful vaccine in quantities sufficient to supply all affected regions, particularly low-resource countries.<ref name="thanh3" />
Industry analysis of past vaccine development shows failure rates of 84–90%.<ref name="thanh3" /><ref name="bio">Liquid error: wrong number of arguments (given 1, expected 2)</ref> 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.<ref name="thanh3" />
To assess the potential for vaccine efficacy, unprecedented computer simulations and new COVID‑19-specific animal models are being developed multinationally during 2020, but these methods remain untested by unknown characteristics of the COVID‑19 virus.<ref name="thanh3" /> Of the confirmed active vaccine candidates, about 70% are being developed by private companies, with the remaining projects under development by academic, government coalitions, and health organizations.<ref name="thanh22" />
Most of the vaccine developers are small firms or university research teams with little experience in successful vaccine design and limited capacity for advanced clinical trial costs and manufacturing without partnership by multinational pharmaceutical companies.<ref name="thanh22" /><ref name="thanh3" />
Historically, the probability of success for an infectious disease vaccine candidate to pass preclinical barriers and reach PhaseI of human testing is 41–57%.<ref name="gouglas2" />
=== Challenges ===
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.<ref name="diamond">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="thanh3" /><ref name="Thorp">Liquid error: wrong number of arguments (given 1, expected 2)</ref> One study found that between 2006 and 2015, the success rate of obtaining approval from PhaseI to successful PhaseIII trials was 16.2% for vaccines,<ref name="bio" /> and CEPI indicates a potential success rate of only 10% for vaccine candidates in 2020 development.<ref name="thanh3" />
Research at universities is obstructed by [[Social distancing|physical distancing]] and closing of laboratories.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
==== Biosafety ====
Early research to assess vaccine efficacy using COVID‑19-specific animal models, such as [[ACE2]]-[[transgenic]] mice, other laboratory animals, and non-human primates, indicates a need for [[biosafety]]-level3 containment measures for handling live viruses, and international coordination to ensure standardized safety procedures.<ref name="diamond" /><ref name="thanh3" />
==== Antibody-dependent enhancement ====
Although the quality and quantity of [[antibody]] production by a potential vaccine is intended to neutralize the COVID‑19 infection, a vaccine may have an unintended opposite effect by causing [[Antibody-dependent enhancement|antibody-dependent disease enhancement]] (ADE), which increases the virus attachment to its target cells and might trigger a [[cytokine storm]] if a vaccinated person is later attacked by the virus.<ref name="diamond" /><ref name="iwasaki">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The vaccine technology platform (for example, [[viral vector]] vaccine, [[Severe acute respiratory syndrome-related coronavirus#Morphology|spike (S) protein]] vaccine or [[protein subunit]] vaccine), vaccine dose, timing of repeat vaccinations for the possible recurrence of COVID‑19 infection, and elderly age are factors determining the risk and extent of ADE.<ref name="diamond" /><ref name="iwasaki" /> The antibody response to a vaccine is a variable of vaccine technologies in development, including whether the vaccine has precision in its mechanism,<ref name="diamond" /> and choice of the route for how it is given ([[Intramuscular injection|intramuscular]], [[Intradermal injection|intradermal]], oral, or nasal).<ref name="iwasaki" />
== Trials ==
[[File:Covid_vaccine_clinical_trial,_Padjajaran_University_(cropped).jpg|link=https://en.wikipedia.org/wiki/File:Covid_vaccine_clinical_trial,_Padjajaran_University_(cropped).jpg|thumb|Volunteer receives CoronaVac injection during Phase III trial by Sinovac in Indonesia.]]
[[File:BNT162b2_vaccine_efficacy_data.png|link=https://en.wikipedia.org/wiki/File:BNT162b2_vaccine_efficacy_data.png|thumb|Cumulative incidence curves for symptomatic COVID‑19 infections after the first dose of the Pfizer-BioNTech vaccine (tozinameran) or placebo in a double-blind clinical trial. (red: placebo; blue: tozinameran)<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>]]
In April 2020, the WHO published an "R&D Blueprint (for the) novel Coronavirus" (Blueprint). The Blueprint 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 Blueprint listed a ''Global Target Product Profile'' (TPP) for COVID‑19, identifying favorable attributes of safe and effective vaccines under two broad categories: "vaccines for the long-term protection of people at higher risk of COVID‑19, such as healthcare workers", and other vaccines to provide rapid-response immunity for new outbreaks.<ref name="who-accel" /> The international TPP team was formed to 1) assess the development of the most promising candidate vaccines; 2) map candidate vaccines and their clinical trial worldwide, publishing a frequently-updated "landscape" of vaccines in development;<ref name="who-tracker">Liquid error: wrong number of arguments (given 1, expected 2)</ref> 3) rapidly evaluate and screen for the most promising candidate vaccines simultaneously before they are tested in humans; and 4) design and coordinate a multiple-site, international [[randomized controlled trial]]the "Solidarity trial" for vaccines<ref name="who-accel" /><ref name="solidarity-vacc"></ref>to enable simultaneous evaluation of the benefits and risks of different vaccine candidates under clinical trials in countries where there are high rates of COVID‑19 disease, ensuring fast interpretation and sharing of results around the world.<ref name="who-accel" /> 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.<ref name="who-accel" />
PhaseI trials test primarily for safety and preliminary dosing in a few dozen healthy subjects, while PhaseII trialsfollowing success in PhaseIevaluate [[immunogenicity]], dose levels (efficacy based on [[Biomarker|biomarkers]]) and adverse effects of the candidate vaccine, typically in hundreds of people.<ref name="Vaccines.gov">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="fda-ddp">Liquid error: wrong number of arguments (given 1, expected 2)</ref> A PhaseI–II trial consists of preliminary safety and immunogenicity testing, is typically randomized, placebo-controlled, while determining more precise, effective doses.<ref name="fda-ddp" /> 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 effect|adverse effects]] at the optimal dose.<ref name="Vaccines.gov" /><ref name="fda-ddp" /> Definition of vaccine safety, efficacy, and [[Clinical endpoint|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.<ref name="cohen6-19">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="cdc-eff">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== Enrollment of participants ===
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 indication|moving target]]" of changing transmission rate across and within countries, forcing companies to compete for trial participants.<ref name="cohen6-19" /> As an example in June, the Chinese vaccine developer Sinovac formed alliances in [[Malaysia]], Canada, the UK, and Brazil among its plans to recruit trial participants and manufacture enough vaccine doses for a possible PhaseIII study in Brazil where COVID‑19 transmission was accelerating during June.<ref name="cohen6-19" /> As the COVID‑19 pandemic within China became more isolated and controlled, Chinese vaccine developers sought international relationships to conduct advanced human studies in several countries, creating competition for trial participants with other manufacturers and the international Solidarity trial organized by the WHO.<ref name="cohen6-19" /> In addition to competition over recruiting participants, clinical trial organizers may encounter people unwilling to be vaccinated due to [[vaccine hesitancy]]<ref name="dube">Liquid error: wrong number of arguments (given 1, expected 2)</ref> or disbelieving the science of the vaccine technology and its ability to prevent infection.<ref name="howard-cnn">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
Having an insufficient number of skilled team members to administer vaccinations may hinder clinical trials that must overcome risks for trial failure, such as recruiting participants in rural or low-density geographic regions, and variations of age, race, ethnicity, or underlying medical conditions.<ref name="cohen6-19" /><ref name="winter">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== Adaptive design for the Solidarity trial ===
A clinical trial design in progress may be modified as an [[Adaptive design (medicine)|"adaptive design"]] if accumulating data in the trial provide early insights about positive or negative efficacy of the treatment.<ref name="pallmann">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="fda-adaptive">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The WHO Solidarity trial of multiple vaccines in clinical studies during 2020, will apply adaptive design to rapidly alter trial parameters across all study sites as results emerge.<ref name="solidarity-vacc" /> Candidate vaccines may be added to the Solidarity trial as they become available if priority criteria are met, while vaccine candidates showing poor evidence of safety or efficacy compared to placebo or other vaccines will be dropped from the international trial.<ref name="solidarity-vacc" />
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.<ref name="solidarity-vacc" /><ref name="pallmann" />
=== Proposed challenge studies ===
[[Human challenge study|Challenge studies]] are a type of clinical trial involving the intentional exposure of the test subject to the condition tested, an approach that can significantly accelerate vaccine development.<ref name="lamb">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="eyal">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="callaway">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="cohen">Liquid error: wrong number of arguments (given 1, expected 2)</ref> Human challenge studies may be ethically controversial because they involve exposing test subjects to dangers beyond those posed by potential [[Side effect|side effects]] of the substance being tested.<ref name="eyal" /><ref name="callaway" /> Challenge studies have been used for diseases less deadly than COVID‑19 infection, such as common influenza, [[typhoid fever]], [[cholera]], and [[malaria]].<ref name="callaway" /><ref name="cohen" /> The World Health Organization has developed a guidance document with criteria for conducting COVID‑19 challenge studies in healthy people, including scientific and ethical evaluation, public consultation and coordination, selection and [[informed consent]] of the participants, and monitoring by independent experts.<ref name="who-challenge">Liquid error: wrong number of arguments (given 1, expected 2)</ref> Beginning in January 2021, dozens of young adult volunteers will be deliberately infected with COVID‑19 in a challenge trial conducted in a London hospital under management by the British government COVID‑19 Vaccine Taskforce.<ref name="call-challenge" /> Once an infection dose of COVID‑19 is identified, two or more of the candidate COVID‑19 vaccines will be tested for effectiveness in preventing infection.<ref name="call-challenge" />
== Authorizations and licensure ==
At the beginning of the COVID‑19 pandemic in early 2020, the WHO issued a guideline as an Emergency Use Listing of new vaccines, a process derived from the 2013–16 [[Western African Ebola virus epidemic|Ebola epidemic]].<ref name="who-eul">Liquid error: wrong number of arguments (given 1, expected 2)</ref> It required that a vaccine candidate developed for a life-threatening emergency be manufactured using GMP and that it complete development according to WHO prequalification procedures.<ref name="who-eul" />
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. In the UK and the EU, companies may use a "rolling review process", supplying data as they become available during Phase III trials, rather than developing the full documentation over months or years at the end of clinical research, as is typical. This rolling process allows the [[Medicines and Healthcare products Regulatory Agency|UK's regulator (MHRA)]] and the European Committee for Medicinal Products for Human Use to evaluate clinical data in real time, enabling a promising vaccine candidate to be approved on a rapid timeline by both the UK's MHRA and the [[European Medicines Agency]] (EMA).<ref name="ema-eau"></ref> A rolling review process for the Moderna vaccine candidate was initiated in October by [[Health Canada]] and the EMA,<ref name="byrne10-19">Liquid error: wrong number of arguments (given 1, expected 2)</ref> and in November in Canada for the Pfizer-BioNTech candidate.<ref name="dangerfield">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In the United States, an [[Emergency Use Authorization]] (EUA) is "a mechanism to facilitate the availability and use of medical countermeasures, including vaccines, during public health emergencies, such as the current COVID‑19 pandemic."<ref name="fda-eua">Liquid error: wrong number of arguments (given 1, expected 2) </ref> Once an EUA is issued by the FDA, the vaccine developer is expected to continue the Phase III clinical trial to finalize safety and efficacy data, leading to application for licensure (approval) in the United States.<ref name="fda-eua" /> In mid-2020, concerns that the FDA might grant a vaccine EUA before full evidence from a Phase III clinical trial was available raised broad concerns about the potential for lowered standards in the face of political pressure.<ref name="malik"></ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="hoffman">Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 8 September 2020, nine leading pharmaceutical companies involved in COVID‑19 vaccine research signed a letter, pledging that they would submit their vaccines for emergency use authorization only after Phase III trials had demonstrated safety and efficacy.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== Early authorizations in China and Russia ===
On 24 June 2020, China approved the CanSino vaccine for limited use in the military and two inactivated virus vaccines for emergency use in high-risk occupations.<ref name=":1" /> On 11 August 2020, Russia announced the approval of its Sputnik V vaccine for emergency use, though one month later only small amounts of the vaccine had been distributed for use outside of the phase 3 trial.<ref name=":2" /> In September, the [[United Arab Emirates]] approved emergency use of [[China National Pharmaceutical Group|Sinopharm]]'s vaccine for healthcare workers,<ref></ref> followed by similar emergency use approval from [[Bahrain]] in November.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== First authorizations of RNA vaccines ===
[[File:Pfizer-BioNTech_COVID-19_vaccine_(2020)_G.jpg|link=https://en.wikipedia.org/wiki/File:Pfizer-BioNTech_COVID-19_vaccine_(2020)_G.jpg|thumb|Pfizer-BioNTech COVID-19 vaccine.]]
The Pfizer-BioNTech partnership submitted an EUA request to the FDA for the mRNA vaccine BNT162b2 (active ingredient [[tozinameran]]) on 20 November 2020.<ref name=":3" /><ref name=":4" /> On 2 December 2020, the United Kingdom's [[Medicines and Healthcare products Regulatory Agency]] (MHRA) gave temporary regulatory approval for the [[Pfizer-BioNTech COVID‑19 vaccine|Pfizer–BioNTech vaccine]],<ref name=":5" /> becoming the first country to approve this vaccine and the first country in the Western world to approve the use of any COVID‑19 vaccine.<ref name="mueller" /><ref name=":6" /> On 8 December 2020, 90-year-old Margaret Keenan received the vaccine at [[University Hospital Coventry]], becoming the first person known to be vaccinated outside of a trial,<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> as the [[COVID‑19 vaccination programme in the United Kingdom|UK's vaccination programme]] began.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> However, other vaccines had been given earlier in Russia.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 11 December 2020, the US [[Food and Drug Administration]] (FDA) granted an Emergency Use Authorization (EUA) for the Pfizer-BioNTech vaccine.<ref name="thomas" /><ref name="pmid 33332292">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The vaccine has subsequently been approved for use by a number of national health authorities.Liquid error: wrong number of arguments (given 1, expected 2) On 19 December 2020, the [[Swissmedic|Swiss Agency for Therapeutic Products (Swissmedic)]] approved the Pfizer-BioNTech vaccine for regular use, two months after receiving the application. This was the first authorization by a [[stringent regulatory authority]] under a standard procedure for any COVID‑19 vaccine.<ref name="Swiss authorization">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 23 December, a 90-year-old [[Lucerne]] resident became the first person to receive the vaccine in continental Europe.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
As of 21 December, many countries and the European Union have authorized or approved the Pfizer-BioNTech COVID‑19 vaccine. [[Bahrain]] and the [[United Arab Emirates]] granted emergency marketing authorization for BBIBP-CorV, manufactured by [[China National Pharmaceutical Group#COVID%E2%80%9119 Vaccine: BBIBP-CorV|Sinopharm]].<ref name="bna" /><ref name="uae" /> In the United Kingdom, 138,000 people had received the Pfizer-BioNTech COVID‑19 vaccine Cominarty by 16 December, during the first week of the [[COVID‑19 vaccination programme in the United Kingdom|UK vaccination programme]].<ref name="graun-138">Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 11 December 2020, the United States [[Food and Drug Administration]] (FDA) granted an [[Emergency Use Authorization]] (EUA) for the Pfizer-BioNTech COVID‑19 vaccine.<ref name="thomas" /> A week later, they granted an EUA for [[mRNA-1273]], the Moderna vaccine.<ref name="CDC ACIP Moderna COVID-19 Vaccine" /><ref name="CNBC 20201219" /> Vaccine manufacturers are awaiting full approvals to name their vaccines.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
Moderna submitted a request for an EUA for [[mRNA-1273]] to the FDA on 30 November 2020.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> On 18 December 2020, the FDA granted an EUA for the Moderna vaccine.<ref name="CDC ACIP Moderna COVID-19 Vaccine" /><ref name="CNBC 20201219" />
=== United Kingdom ===
The [[Medicines and Healthcare products Regulatory Agency|UK's regulator (MHRA)]] gave the first approval to the [[AZD1222|Oxford/AstraZeneca]] vaccine on 30 December 2020, as their second vaccine to enter the [[COVID‑19 vaccination programme in the United Kingdom|national rollout]].<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== Australia ===
In October 2020, the Australian [[Therapeutic Goods Administration]] (TGA) granted provisional determinations to AstraZeneca Pty Ltd in relation to its COVID‑19 vaccine, ChAdOx1-S [recombinant] and to Pfizer Australia Pty Ltd in relation to its COVID‑19 vaccine, [[Tozinameran|BNT162b2]] [mRNA].<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> Janssen Cilag Pty Ltd was granted a provisional determination in relation to its COVID‑19 vaccine, Ad26.COV2.S, in November 2020.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
=== European Union ===
In October 2020, the [[Committee for Medicinal Products for Human Use]] (CHMP) started 'rolling reviews' of the vaccines known as ''COVID‑19 Vaccine AstraZeneca'' (ChAdOx1-SARS-CoV-2) and ''Pfizer-BioNTech COVID‑19 Vaccine'' ([[Tozinameran|BNT162b2]]).<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref> The EMA released an update on the status of its rolling review of the COVID‑19 Vaccine AstraZeneca in December 2020, after the UK granted a temporary authorization of supply for the vaccine.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In November 2020, the EMA published a safety monitoring plan and guidance on risk management planning (RMP) for COVID‑19 vaccines.<ref name="EMA PR 20201113">Liquid error: wrong number of arguments (given 1, expected 2) Text was copied from this source which is European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> The plan outlines how relevant new information emerging after the authorization and uptake of COVID‑19 vaccines in the pandemic situation will be collected and promptly reviewed.<ref name="EMA PR 20201113" /> All RMPs for COVID‑19 vaccines will be published on the EMA's website.<ref name="EMA PR 20201113" /> The EMA published guidance for developers of potential COVID‑19 vaccines on the clinical evidence to include in marketing authorization applications.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In November 2020, the CHMP started a rolling review of the Moderna vaccine for COVID‑19 known as mRNA-1273.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In December 2020, the EMA received application for conditional marketing authorizations (CMA) for the mRNA vaccines ''BNT162b2'' and ''mRNA1273'' (''Moderna Covid‑19 vaccine'').<ref name="EMA mRNA1273 application">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="EMA BNT162b2 application">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The assessments of the vaccines are scheduled to proceed under accelerated timelines with the possibility of opinions issued within weeks.<ref name="EMA mRNA1273 application" /><ref name="EMA BNT162b2 application" /><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
In December 2020, the CHMP started a rolling review of the Ad26.COV2.S COVID‑19 vaccine from Janssen-Cilag International N.V.<ref name="EU Ad26.COV2.S rolling review">Liquid error: wrong number of arguments (given 1, expected 2)</ref>
On 21 December 2020, the CHMP recommended granting a conditional marketing authorization for the Pfizer-BioNTech COVID‑19 vaccine, Comirnaty (active ingredient tozinameran), developed by BioNTech and Pfizer.<ref name="EU PR 20201221">Liquid error: wrong number of arguments (given 1, expected 2)</ref><ref name="Comirnaty: Pending EC decision">Liquid error: wrong number of arguments (given 1, expected 2)</ref> The recommendation was accepted by the [[European Commission]] the same day.<ref name="EU PR 20201221" /><ref name="EU statement"></ref>
In January 2021, the EMA received an application for conditional marketing authorization (CMA) for the COVID‑19 vaccine known as ''[[AZD1222|COVID‑19 Vaccine AstraZeneca]]'', developed by AstraZeneca and Oxford University.<ref>Liquid error: wrong number of arguments (given 1, expected 2)</ref>
== References ==
[[Category:COVID-19 vaccines| ]]
[[Category:Medical research]]
[[Category:Medical responses to the COVID-19 pandemic]]
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