Is your Sperm a COVID 19 Vaccine?

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COVID‑19 vaccine is a vaccine intended to provide acquired immunity against COVID-19. Prior to the COVID-19 pandemic, work to develop a vaccine against the coronavirus diseases SARS and MERS had established knowledge about the structure and function of coronaviruses, which accelerated development during early 2020 of varied technology platforms for a COVID‑19 vaccine.

By mid-December 2020, 57 vaccine candidates were in clinical research, including 40 in Phase I–II trials and 17 in Phase II–III trials. In Phase III trials, several COVID-19 vaccines demonstrated efficacy as high as 95% in preventing symptomatic COVID-19 infections.[1] National regulatory authorities have approved five vaccines for public use: tozinameran from Pfizer–BioNTech, BBIBP-CorV from Sinopharm, CoronaVac from Sinovac, mRNA-1273 from Moderna, and Gam-COVID-Vac from the Gamaleya Research Institute.

Pfizer, Moderna, and AstraZeneca predicted a manufacturing capacity of 5.3 billion doses in 2021, which could be used to vaccinate about 3 billion people (as the vaccines require two doses for a protective effect against COVID-19). By December, more than 10 billion vaccine doses had been preordered by countries,[2] with about half of the doses purchased by high-income countries comprising only 14% of the world’s population.[3] Many countries have implemented phased distribution plans that prioritize those at highest risk of complications such as the elderly and those at high risk of exposure and transmission such as healthcare workers.[4]

Planning and investment

During 2020, major changes in the overall effort of developing COVID‑19 vaccines since early in the year have been the increasing number of collaborations of the multinational pharmaceutical industry with national governments, and the diversity and growing number of biotechnology companies in many countries focusing on a COVID-19 vaccine.[5] According to CEPI, the general geographic distribution of COVID‑19 vaccine development involves organizations in North America having about 40% of the world’s COVID-19 vaccine research, compared with 30% in Asia and Australia, 26% in Europe, and a few projects in South America and Africa.[5][6]

Commitment to first-in-human testing of a vaccine candidate represents a substantial capital cost for vaccine developers, estimated to be from US$14 million to US$25 million for a typical Phase I trial program, but possibly as much as US$70 million.[7][8] For comparison, during the Ebola virus epidemic of 2013–16, there were 37 vaccine candidates in urgent development, but only one eventually succeeded as a licensed vaccine, involving a total cost to confirm efficacy in Phase II–III trials of about US$1 billion.[7]

International organizations

Access to COVID-19 Tools (ACT) Accelerator and COVAX

A multinational collaboration, including the World Health Organization (WHO), the Coalition for Epidemic Preparedness Innovations (CEPI), GAVI, the Gates Foundation, and governments, formed the Access to COVID-19 Tools (ACT) Accelerator, to raise financial support of accelerated research and development, production, and globally-equitable access to COVID-19 tests, therapies, and licensing of vaccines, which are in a specific development program called the “COVAX Pillar”.[9][10] The COVAX Pillar has the goal of facilitating licensure of several COVID-19 vaccines, influencing equitable pricing, and providing equal access for up to 2 billion doses by the end of 2021 to protect frontline healthcare workers and people with high-risk of COVID-19 infection, particularly in low-to-middle income countries.[11][12]

As of December 2020, US$2.4 billion had been raised for the overall ACT Accelerator, with nine vaccine candidates being funded by COVAX and CEPI – the world’s largest COVID-19 vaccine portfolio – with 189 countries committed to the eventual deployment plan.[13][14] Earlier in 2020, the WHO had a telethon which raised US$8 billion in pledges from forty countries to support rapid development of vaccines.[15]

In July, the WHO announced that 165 countries, representing up to 60% of the world population, had agreed to a WHO COVAX plan for fair and equitable distribution of an eventual licensed vaccine, assuring that each participating country would receive a guaranteed share of doses to vaccinate the most vulnerable 20% of its population by the end of 2021.[16]

The Global Research Collaboration for Infectious Disease Preparedness (GLoPID-R) is working closely with the WHO and member states to identify priorities for funding specific research needed for a COVID‑19 vaccine, coordinating among the international funding and research organizations to maintain updated information on vaccine progress and avoid duplicate funding.[17][18] The International Severe Acute Respiratory and Emerging Infection Consortium is organizing and disseminating clinical information on COVID‑19 research to inform public health policy on eventual vaccine distribution.[19]

On 4 June, a virtual summit was coordinated from London, UK, among private and government representatives of 52 countries, including 35 heads of state from G7 and G20 nations, to raise US$8.8 billion in support of the Global Alliance for Vaccines and Immunisation (GAVI) to prepare for COVID‑19 vaccinations of 300 million children in under-developed countries through 2025.[20] Major contributions were US$1.6 billion from The Gates Foundation[21] and GB£330 million per year over five years by the British government (approximately US$2.1 billion in June 2020).[20]

In December, the Gates Foundation donated another US$250 million to the WHO ACT Accelerator to “support the delivery of new COVID-19 tests, treatments, and vaccines, particularly in low- and middle-income countries” during 2021, making the Foundation’s total donation of US$1.75 billion toward the COVID-19 response.[22][23]

Coalition for Epidemic Preparedness Innovations

A multinational organization formed in 2017, CEPI is working with international health authorities and vaccine developers to create vaccines for preventing epidemics.[12] CEPI has organized a US$2 billion fund in a global partnership between public, private, philanthropic, and civil society organizations for accelerated research and clinical testing of nine COVID-19 vaccine candidates, with the 2020–21 goal of supporting several candidate vaccines for full development to licensing.[5][24][13] The United Kingdom, Canada, Belgium, Norway, Switzerland, Germany and the Netherlands had already donated US$915 million to CEPI by early May.[15][25] The Gates Foundation, a private charitable organization dedicated to vaccine research and distribution, is donating US$250 million in support of CEPI for research and public educational support on COVID‑19 vaccines.[26][27]

Over 2020 throughout the pandemic, CEPI was funding the development of nine vaccine candidates in a portfolio deliberately made diverse across different vaccine technologies to minimize the typically high risk of failure inherent in vaccine development.[13][28] As of December, the vaccine research organizations and programs being supported by CEPI were Clover Biopharmaceuticals (vaccine candidate, SCB-2019), CureVacInovioInstitut Pasteur (vaccine candidate, MV-SARS-CoV-2), ModernaNovavaxAZD1222 (University of Oxford-AstraZeneca), Hong Kong University, and SK bioscience (vaccine candidate, GBP510).[13][29][30]

National governments

National governments dedicating resources for national or international investments in vaccine research, development, and manufacturing beginning in 2020, included the Canadian government which announced CA$275 million in funding for 96 research vaccine research projects at Canadian companies and universities, with plans to establish a “vaccine bank” of several new vaccines that could be used if another coronavirus outbreak occurs.[31][32] A further investment of CA$1.1 billion was added to support clinical trials in Canada and develop manufacturing and supply chains for vaccines.[18] On 4 May, the Canadian government committed CA$850 million to the WHO’s live streaming effort to raise US$8 billion for COVID‑19 vaccines and preparedness.[33]

In China, the government is providing low-rate loans to a vaccine developer through its central bank, and has “quickly made land available for the company” to build production plants.[25] As of June 2020, six of the eleven COVID‑19 vaccine candidates in early-stage human testing were developed by Chinese organizations.[26] 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, while prioritizing rapid evidence of efficacy over safety.[34] On 18 May, China had pledged US$2 billion to support overall efforts by the WHO for programs against COVID‑19.[35] On 22 July, China additionally announced that it plans to provide a US$1 billion loan to make its vaccine accessible for countries in Latin America and the Caribbean.[36] On 24 August, Chinese Premier Li Keqiang announced it would provide five Southeast Asian countries of Cambodia, Laos, Myanmar, Thailand and Vietnam priority access to the vaccine once it was fully developed.[37]

Among European Union countries, France announced a US$4.9 million investment in a COVID‑19 vaccine research consortium via CEPI involving the Institut Pasteur, Themis Bioscience (ViennaAustria), and the University of Pittsburgh, bringing CEPI’s total investment in COVID‑19 vaccine development to US$480 million by May.[38][39] In March, the European Commission made an €80 million investment in CureVac, a German biotechnology company, to develop a mRNA vaccine.[40] The German government announced a separate €300 million investment in CureVac in June.[41] Belgium, Norway, Switzerland, Germany, and the Netherlands have been major contributors to the CEPI effort for COVID‑19 vaccine research in Europe.[25]

US Government Accountability Office diagram comparing a traditional vaccine development timeline to a possible expedited timeline

In April, the British government formed a COVID‑19 vaccine task force to stimulate British efforts for rapidly developing a vaccine through collaborations of industry, universities, and government agencies across the vaccine development pipeline, including clinical trial placement at British hospitals, regulations for approval, and eventual manufacturing.[42] The vaccine development initiatives at the University of Oxford and Imperial College of London were financed with GB£44 million in April.[43][44]

The United States Biomedical Advanced Research and Development Authority (BARDA), a federal agency that funds disease-fighting technology, announced investments of nearly US$1 billion to support American COVID‑19 vaccine development, and preparation for manufacturing the most promising candidates. On 16 April, BARDA made a US$483 million investment in the vaccine developer, Moderna and its partner, Johnson & Johnson.[25][45] BARDA has an additional US$4 billion to spend on vaccine development, and will have roles in other American investment for development of six to eight vaccine candidates to be in clinical studies over 2020–21 by companies such as Sanofi Pasteur and Regeneron.[45][46] On 15 May, the US government announced federal funding for a fast-track program called Operation Warp Speed, which has the goals of placing diverse vaccine candidates in clinical trials by the fall of 2020, and manufacturing 300 million doses of a licensed vaccine by January 2021. The project chief advisor is Moncef Slaoui and its chief operating officer is Army General Gustave Perna.[47][48] In June, the Warp Speed team said it would work with seven companies developing COVID‑19 vaccine candidates: ModernaJohnson & JohnsonMerckPfizer, and the University of Oxford in collaboration with AstraZeneca, as well as two others,[49] although Pfizer later stated that “all the investment for R&D was made by Pfizer at risk.”[50]

Pharmaceutical companies

Large pharmaceutical companies with experience in making vaccines at scale, including Johnson & Johnson, AstraZeneca, and GlaxoSmithKline (GSK), formed alliances with biotechnology companies, national governments, and universities to accelerate progression to an effective vaccine.[25][26] To combine financial and manufacturing capabilities for a pandemic adjuvanted vaccine technology, GSK joined with Sanofi in an uncommon partnership of multinational companies to support accelerated vaccine development.[51]

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.[52][53][54][55] 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.[52][26][54] 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.[55] AstraZeneca stated that initial pricing of its vaccine would not include a profit margin for the company while the pandemic was still expanding.[55]

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 proves safe and effective, reportedly increasing the company’s total production capacity to over 2 billion doses per year.[56] 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.[52][25][26][53] The multinational pharmaceutical company Pfizer indicated it was not interested in a government partnership, which would be a “third party” slowing progress in Pfizer’s vaccine program.[57] Further, there are concerns that rapid-development programs – like the Operation Warp Speed plan of the United States – are choosing vaccine candidates mainly for their manufacturing advantages to shorten the development timeline, rather than for the most promising vaccine technology having safety and efficacy.[57]

Compressed timelines

Geopolitical issues, safety concerns for vulnerable populations, and manufacturing challenges for producing billions of doses are compressing schedules to shorten the standard vaccine development timeline, in some cases combining clinical trial steps over months, a process typically conducted sequentially over years.[26] As an example, Chinese vaccine developers and the government Chinese Center for Disease Control and Prevention began their efforts in January 2020,[58] and by March were pursuing numerous candidates on short timelines, with the goal to showcase Chinese technology strengths over those of the United States, and to reassure the Chinese people about the quality of vaccines produced in China.[26][59]

In the haste to provide a vaccine on a rapid timeline for the COVID‑19 pandemic, developers and governments are accepting a high risk of “short-circuiting” the vaccine development process,[25] with one industry executive saying: “The crisis in the world is so big that each of us will have to take maximum risk now to put this disease to a stop”.[25] Multiple steps along the entire development path are evaluated, including the level of acceptable toxicity of the vaccine (its safety), targeting vulnerable populations, the need for vaccine efficacy breakthroughs, the duration of vaccination protection, special delivery systems (such as oral or nasal, rather than by injection), dose regimen, stability and storage characteristics, emergency use authorization before formal licensing, optimal manufacturing for scaling to billions of doses, and dissemination of the licensed vaccine.[60][61] From Phase I clinical trials, 84–90%[6][62] of vaccine candidates fail to make it to final approval during development, and from Phase III, 25.7% fail[62] – the investment by a manufacturer in a vaccine candidate may exceed US$1 billion and end with millions of useless doses.[60][25][26]

As the pandemic expands during 2020, research at universities is obstructed by physical distancing and closing of laboratories.[63][64] Globally, supplies critical to vaccine research and development are increasingly scarce due to international competition or national sequestration.[34] Timelines for conducting clinical research – normally a sequential process requiring years – are being compressed into safety, efficacy, and dosing trials running simultaneously over months, potentially compromising safety assurance.[25][26]

Development

Background

Prior to COVID-19, a vaccine for an infectious disease had never before been produced in less than several years, and no vaccine existed for preventing a coronavirus infection in humans.[60] However, vaccines have been produced against several animal diseases caused by coronaviruses, including as of 2003 infectious bronchitis virus in birds, canine coronavirus, and feline coronavirus.[65] Previous projects to develop vaccines for viruses in the family Coronaviridae that affect humans have been aimed at severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Vaccines against SARS[66] and MERS[67] have been tested in non-human animals.

According to studies published in 2005 and 2006, the identification and development of novel vaccines and medicines to treat SARS was a priority for governments and public health agencies around the world at that time.[68][69][70] As of 2020, there is no cure or protective vaccine proven to be safe and effective against SARS in humans.[71][72]

There is also no proven vaccine against MERS.[73] When MERS became prevalent, it was believed that existing SARS research may provide a useful template for developing vaccines and therapeutics against a MERS-CoV infection.[71][74] As of March 2020, there was one (DNA based) MERS vaccine which completed Phase I clinical trials in humans,[75] and three others in progress, all of which are viral-vectored vaccines: two adenoviral-vectored (ChAdOx1-MERS, BVRS-GamVac), and one MVA-vectored (MVA-MERS-S).[76]

Early development

After the coronavirus was detected in December 2019,[77] the genetic sequence of COVID‑19 was published on 11 January 2020, triggering an urgent international response to prepare for an outbreak and hasten development of a preventive vaccine.[6][52][78]

In February 2020, the World Health Organization (WHO) said it did not expect a vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus, to become available in less than 18 months.[79] 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,[80] with four vaccine candidates entering human evaluation in March (see the table of clinical trials started in 2020, below).[6][24]

In April 2020, the WHO estimated a total cost of US$8 billion to develop a suite of three or more vaccines having different technologies and distribution.[80]

By April 2020, “almost 80 companies and institutes in 19 countries” were working on this virtual gold rush.[81] 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 Phase II–III trials, and three should be streamlined through regulatory and quality assurance for eventual licensing at a total cost of at least US$2 billion.[5][24][60] Another analysis estimates 10 candidates will need simultaneous initial development, before a select few are chosen for the final path to licensing.[60]

In July 2020, Anglo-American intelligence and security organisations of the respective governments and armed forces, as the UK’s National Cyber Security Centre, together with the Canadian Communications Security Establishment, the United States Department for Homeland Security 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.[82]

Preclinical research

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.[83] 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.[6]

Industry analysis of past vaccine development shows failure rates of 84–90%.[6][62] 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.[6]

To assess 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.[6] 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.[5]

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.[5][6]

Historically, the probability of success for an infectious disease vaccine candidate to pass preclinical barriers and reach Phase I of human testing is 41–57%.[7]

Technology platforms

Potential candidates for forming SARS-CoV-2 proteins to prompt an immune response

As of September 2020, nine different technology platforms – with the technology of numerous candidates remaining undefined – were under research and development to create an effective vaccine against COVID‑19.[5] Most of the platforms of vaccine candidates in clinical trials are focused on the coronavirus spike protein and its variants as the primary antigen of COVID‑19 infection.[5] Platforms being developed in 2020 involved nucleic acid technologies (nucleoside-modified messenger RNA and DNA), non-replicating viral vectorspeptidesrecombinant proteins, live attenuated viruses, and inactivated viruses.[60][6][5][84]

Many vaccine technologies being developed for COVID‑19 are not like vaccines already in use to prevent influenza, but rather are using “next-generation” strategies for precision on COVID‑19 infection mechanisms.[6][5][84] Vaccine platforms in development may improve flexibility for antigen manipulation and effectiveness for targeting mechanisms of COVID‑19 infection in susceptible population subgroups, such as healthcare workers, the elderly, children, pregnant women, and people with existing weakened immune systems.[6][5]

COVID‑19 vaccine technology platforms, December 2020[85]
Molecular platform[i] Total number
of candidates
Number of candidates
in human trials
Inactivated virus
19
5[ii]
Non-replicating viral vector
35
4[ii]
RNA-based
36
3[ii]
Protein subunit
80
2[ii]
DNA-based
23
2[ii]
Virus-like particle
19
1[ii]
Replicating viral vector
23
0
Live attenuated virus
4
0
  1. ^ Technologies for dozens of candidates are unannounced or “unknown”.[85]
  2. Jump up to:a b c d e f One or more candidates in Phase II or Phase II–III trials.

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.[84][6][86] One study found that between 2006 and 2015, the success rate of obtaining approval from Phase I to successful Phase III trials was 16.2% for vaccines,[62] and CEPI indicates a potential success rate of only 10% for vaccine candidates in 2020 development.[6]

An April 2020 CEPI report stated: “Strong international coordination and cooperation between vaccine developers, regulators, policymakers, funders, public health bodies and governments will be needed to ensure that promising late-stage vaccine candidates can be manufactured in sufficient quantities and equitably supplied to all affected areas, particularly low-resource regions.”[6]

Biosafety

Early research to assess vaccine efficacy using COVID‑19-specific animal models, such as ACE2transgenic mice, other laboratory animals, and non-human primates, indicates a need for biosafety-level 3 containment measures for handling live viruses, and international coordination to ensure standardized safety procedures.[84][6]

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 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.[84][87] The vaccine technology platform (for example, viral vector vaccine, 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.[84][87] The antibody response to a vaccine is a variable of vaccine technologies in development, including whether the vaccine has precision in its mechanism,[84] and choice of the route for how it is given (intramuscularintradermal, oral, or nasal).[87]

Cost

An effective vaccine for COVID‑19 could save trillions of dollars in global economic impact, according to one expert, and would, therefore, make any price tag in the billions look small in comparison.[88] In early stages of the pandemic, it was not known if it would be possible to create a safe, reliable and affordable vaccine for this virus, and it was not known exactly how much the vaccine development could cost.[60][52][26] There was a possibility that billions of dollars could be invested without success.[25]

Once an effective vaccine would be developed, billions of doses would need to be manufactured and distributed worldwide. In April 2020, the Gates Foundation estimated that manufacturing and distribution could cost as much as US$25 billion.[89] On 4 May 2020, the European Commission organized and held a video conference of world leaders, at which US$8 billion was raised for COVID‑19 vaccine development.[90]

As of November 2020, companies subsidized under the United States’ Operation Warp Speed program have set initial pricing at US$19.50 to US$25 per dose, in line with the influenza vaccine.[91] In December 2020, a Belgian politician briefly published the confidential prices agreed between vaccine producers and the EU:[92]

Manufacturer EU price per dose[93]
AstraZeneca €1.78
Johnson&Johnson US$8.50
Sanofi/GSK €7.56
Pfizer/BioNTech €12.00
CureVac €10.00
Moderna US$18.00

Rollout

Different vaccines have different shipping and handling requirements. For example, the Pfizer/BioNTech vaccine tozinameran (Pfizer-BioNTech COVID-19 Vaccine) must be shipped and stored between −80 and −60 °C (−112 and −76 °F),[94] must be used within five days of thawing,[94] and has a minimum order of 975 doses, making it unlikely to be rolled out in settings other than large, well-equipped hospitals.[95] The Moderna COVID-19 Vaccine vials require storage above −40 °C (−40 °F) and between −25 and −15 °C (−13 and 5 °F).[96] Once refrigerated, the Moderna COVID-19 Vaccine can be kept between 2 and 8 °C (36 and 46 °F) for up to 30 days.[96]

Trials

Volunteer receives CoronaVac injection during Phase III trial by Sinovac in Indonesia.

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.[80] 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;[97] 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[80][98] – 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.[80] The WHO vaccine coalition will prioritize which vaccines should go into Phase II and III clinical trials, and determine harmonized Phase III protocols for all vaccines achieving the pivotal trial stage.[80]

Enrollment of participants

Vaccine developers have to invest resources internationally to find enough participants for Phase II–III clinical trials when the virus has proved to be a “moving target” of changing transmission rate across and within countries, forcing companies to compete for trial participants.[99] 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 Phase III study in Brazil where COVID‑19 transmission was accelerating during June.[99] 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.[99] In addition to competition over recruiting participants, clinical trial organizers may encounter people unwilling to be vaccinated due to vaccine hesitancy[100] or disbelieving the science of the vaccine technology and its ability to prevent infection.[101]

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.[99][102]

Adaptive design for the Solidarity trial

A clinical trial design in progress may be modified as an “adaptive design” if accumulating data in the trial provide early insights about positive or negative efficacy of the treatment.[103][104] 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.[98] 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.[98]

Adaptive designs within ongoing Phase II–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.[98][103]

Proposed challenge studies

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.[105][106][107][108] Human challenge studies may be ethically controversial because they involve exposing test subjects to dangers beyond those posed by potential side effects of the substance being tested.[106][107] Challenge studies have been used for diseases less deadly than COVID‑19 infection, such as common influenza, typhoid fevercholera, and malaria.[107][108] 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.[109] 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.[110] 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.[110]

Vaccines

As of 21 December, many countries and the European Union[111] have authorized or approved tozinameran, the Pfizer–BioNTech vaccine. Bahrain and the United Arab Emirates granted emergency marketing authorization for BBIBP-CorV, manufactured by Sinopharm.[112][113] In the United Kingdom, 138,000 people had received tozinameran by 16 December during the first week of the UK vaccination programme.[114] On 11 December 2020, the United States Food and Drug Administration (FDA) granted an Emergency Use Authorization (EUA) for tozinameran.[115] A week later, they granted an EUA for mRNA-1273, the Moderna vaccine.[116][117][118]

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 initiation of Phase I safety studies in healthy people.[5] 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.[5]

Phase I trials test primarily for safety and preliminary dosing in a few dozen healthy subjects, while Phase II trials – following success in Phase I – evaluate immunogenicity, dose levels (efficacy based on biomarkers) and adverse effects of the candidate vaccine, typically in hundreds of people.[119][120] A Phase I–II trial consists of preliminary safety and immunogenicity testing, is typically randomized, placebo-controlled, while determining more precise, effective doses.[120] Phase III trials typically involve more participants at multiple sites, include a control group, and test effectiveness of the vaccine to prevent the disease (an “interventional” or “pivotal” trial), while monitoring for adverse effects at the optimal dose.[119][120] Definition of vaccine safety, efficacy, and clinical endpoints in a Phase III 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.[99][121][122]

Approved vaccines

Approved vaccines for emergency use or full authorization
Vaccine candidates,
developers, and sponsors
Technology Current phase (participants)
design
Completed phase[a] (participants)
Immune response
EUA Full authorization
Ad5-nCoV
CanSino Biologics, Beijing Institute of Biotechnology of the Academy of Military Medical Sciences, NPO Petrovax[123][b]
Recombinant adenovirus type 5 vector Phase III (40,000)
global multi-center, randomized, double-blind, placebo-controlled to evaluate efficacy, safety and immunogenicity.
Location(s): China, ArgentinaChile,[125] Mexico,[126] Pakistan,[127] Russia,[123] Saudi Arabia[128][129]
Duration: Mar. – Dec. 2020, China; Sep. 2020 – Dec. 2021, Pakistan; Sep. 2020 – Nov. 2020, Russia[123]
Phase II (508)
Neutralizing antibody and T cell responses[130]
Approved

BBIBP-CorV[133]
Sinopharm: Beijing Institute of Biological Products, Wuhan Institute of Biological Products
Inactivated SARS-CoV-2 (vero cells) Phase III (48,000)
Randomized, double-blind, parallel placebo-controlled, to evaluate safety and protective efficacy.Positive results from an interim analysis were announced by the UAE on 9 December 2020 with an efficacy of 86%.[134][135]
Location(s): UAEBahrainJordan,[136] Argentina,[137] Morocco,[138] Peru[139]
Duration: Jul 2020 – Jul 2021
Phase I–II (320)
Neutralizing antibodies at day 14 after 2 injections[140]
Location(s): China
Duration: Apr 2020 – Jun 2020
Approved

Approved

CoronaVac[145][146][147]
Sinovac
Inactivated SARS-CoV-2 Phase III (33,620)
Double-blind, randomized, placebo-controlled to evaluate efficacy and safety.Positive results from an interim analysis were announced by Brazil on 23 December 2020 and Turkey on 24 December 2020.[148][149]
Location(s): Brazil (15,000);[150] Chile (3,000);[151] Indonesia (1,620); Turkey (13,000)[152]
Duration: Jul 2020 – Oct 2021 in Brazil; Aug 2020 – Jan 2021 in Indonesia
Phase II (600)
Immunogenicity eliciting 92% seroconversion at lower dose and 98% at higher dose after 14 days[153]
Location(s): China
Duration: May 2020 –
Approved

Gam-COVID-Vac (Sputnik V)
Gamaleya Research Institute of Epidemiology and Microbiology; trade name: Sputnik V
Non-replicating viral vector (adenovirus) Phase III (40,000)
Randomized double-blind, placebo-controlled to evaluate efficacy, immunogenicity, and safety[155]
Location(s): Russia, India[156][157]
Duration: Aug 2020 – May 2021
Phase I–II (76)
Neutralizing antibody and T cell responses.[158]
Location(s): Russia
Duration: Jun 2020[158] – Sep 2020
Approved

mRNA-1273[162][163]
ModernaNIAIDBARDA
Lipid nanoparticle dispersion containing modRNA Phase III (30,000)
Interventional; randomized, placebo-controlled study for efficacy, safety, and immunogenicity.Positive results from an interim analysis were announced on 15 November 2020.[164]
Location(s): United States
Duration: Jul 2020 – Oct 2022
Phase I–II (720)[165][166]
Dose-dependent neutralizing antibody response on two-dose schedule; undetermined durability.[167][168][169]
Location(s): United States
Duration: Mar 2020 – Nov 2021
Approved

Tozinameran[172][173][174]
BioNTechPfizerFosun Pharma
modRNA Phase III (43,448)[175]Positive results from an interim analysis were announced on 18 November 2020[176] and published on 10 December 2020 reporting an overall efficacy of 95%.[177][178]
Randomized, placebo-controlled
Location(s): Germany, United States
Duration: Jul 2020 – Nov 2020[179][180]
Phase I–II (45)
Strong RBD-binding IgG and neutralizing antibody response peaked 7 days after a booster dose, robust CD4+ and CD8+ T cell responses, undetermined durability[181][182]
Duration: May. 2020 –
Approved

Approved

Vaccine candidates

COVID‑19 candidate vaccines in Phase I–III trials[85][215][97]
Vaccine candidates,
developers, and sponsors
Technology Current phase (participants)
design
Completed phase[c] (participants)
Immune response
EUA Full authorization
AZD1222[d][e][219][220][221]
University of OxfordAstraZeneca
Modified chimpanzee adenovirus vector (ChAdOx1) Phase III (30,000)
Interventional; randomized, placebo-controlled study for efficacy, safety, and immunogenicity.[222]Positive results from an interim analysis of four ongoing trials were announced on 23 November 2020 and published on 8 December 2020.[223] Overall efficacy was 70%, ranging from 62% to 90% with different dosing regimens, with a peer-reviewed safety profile.[223]
Location(s): Brazil (5,000),[224] United Kingdom, India[225]
Duration: May 2020 – Aug 2021
Phase I–II (543)
Spike-specific antibodies at day 28; neutralizing antibodies after a booster dose at day 56[226]
Pending

Pending

Ad26.COV2.S[232][233]Janssen Pharmaceutica (Johnson & Johnson), BIDMC Non-replicating viral vector (adenovirus serotype 26) Phase III (40,000)
Randomized, double-blinded, placebo-controlledTemporarily paused on 13 October 2020, due to an unexplained illness in a participant.[234] Johnson & Johnson announced, on 23 October, that they are preparing to resume the trial in the US.[235][236]
Location(s): United States, Argentina, Brazil, Chile, Colombia, Mexico, Peru, Philippines, South Africa and Ukraine
Duration: Jul 2020 – 2023
Phase I–II (1,045) Pending

NVX-CoV2373[239]
Novavax
SARS-CoV-2 recombinant spike protein nanoparticle with adjuvant Phase III (15,000)
Randomised, observer-blinded, placebo-controlled trial[240]
Location(s): UK, India[241]
Duration: Sep 2020 – Jan 2021
Phase I–II (131) IgG and neutralizing antibody response with adjuvant after booster dose[242] Pending

BBV152 (Covaxin)Bharat BiotechIndian Council of Medical Research Inactivated SARS-CoV-2 Phase III (25,800)
Randomised, observer-blinded, placebo-controlled[244]
Location(s): India
Duration: Nov 2020 – Mar 2022
Phase I (375) Dose-dependent neutralizing antibody response on two-dose schedule.
Pending Phase II reports[245]
Pending

CoVLP[247]MedicagoGSK Recombinantplant-based virus-like particles[f] with GSK adjuvant Phase II–III (30,612)
Event-driven, randomized, observer blinded, placebo-controlled[249]
Location(s): Canada
Duration: Nov 2020 – Apr 2022
Phase I (180)
Neutralizing antibodies at day 42 after the first injection (day 21 after the second injection) were at levels 10x that of COVID-19 survivors.
ZF2001 (RBD-Dimer)[85]
Anhui Zhifei Longcom Biopharmaceutical Co. Ltd.
Recombinant subunit vaccine Phase III (29,000)
randomized, double-blind, placebo-controlled[250]
Location(s): China, Ecuador, Indonesia, Malaysia, Pakistan, Uzbekistan [251][252]
Duration: Dec 2020 – Apr 2022
Phase II (900)
Interventional; randomized, double-blind, placebo-controlled[253]
Location(s): Chongqing
Duration: Jun 2020 – Sep 2021
Zorecimeran (CVnCoV)
CureVacCEPI
modRNA Phase III (36,500)[254]
Phase 2b/3: Multicenter efficacy and safety trial in adults
Location(s): Argentina, Belgium, Colombia, Dominican Republic, France, Germany, Mexico, Netherlands, Panama, Peru, Spain
Duration: Nov 2020 – ?
Phase I–II (944)[255][256]
Phase 1 (284): Partially blind, controlled, dose-escalation to evaluate safety, reactogenicity and immunogenicity.Phase 2a (660):Partially observer-blind, multicenter, controlled, dose-confirmation.
Location(s): Belgium (P1), Germany (P1), Panama (2a), Peru (2a)
Duration: Jun 2020 – Oct 2021
INO-4800[g][257][258]
InovioCEPIKorea National Institute of HealthInternational Vaccine Institute
DNA plasmid delivered by electroporation Phase I–II (40)
Location(s): United States, South Korea
Duration: Apr–Nov 2020
Pending Phase I report
EpiVacCorona[259]
Vector
Vaccine based on peptide antigens[259] Phase I–II (100)
Simple, blind, placebo-controlled, randomized study of safety, reactogenicity and immunogenicity[259]
Location(s): Russia
Duration: Jul 2020[259] – ?
Pending Phase I–II report
Unnamed[260]
Chinese Academy of Medical Sciences
Inactivated SARS-CoV-2 Phase I–II (942)
Randomized, double-blinded, single-center, placebo-controlled
Location(s): Chengdu
Duration: Jun 2020 – Sep 2021
AG0301-COVID‑19[261]
AnGes Inc.,[262] AMED
DNA plasmid Phase I–II (30)
Non-randomized, single-center, two doses
Location(s): Osaka
Duration: Jun 2020 – Jul 2021
Lunar-COV19/ARCT-021[263][264]Arcturus Therapeutics mRNA Phase I–II (92)
Randomized, double-blinded
Location(s): Singapore
Duration: Aug 2020 – ?
COVID‑19/aAPC[265]
Shenzhen Genoimmune Medical Institute[266]
Lentiviral vector with minigene modifying aAPCs Phase I (100)
Location(s): Shenzhen
Duration: Mar 2020 – 2023
LV-SMENP-DC[267]
Shenzhen Genoimmune Medical Institute[266]
Lentiviral vector with minigene modifying DCs Phase I (100)
Location(s): Shenzhen
Duration: Mar 2020 – 2023
LNP-nCoVsaRNA[268]
MRC clinical trials unit at Imperial College London
mRNA Phase I (105)
Randomized trial, with dose escalation study (15) and expanded safety study (at least 200)
Location(s): United Kingdom
Duration: Jun 2020 – Jul 2021
ZyCoV-D[269]
Cadila Healthcare
DNA plasmid expressing SARS-CoV-2 S protein Phase I–II (1,000)
Interventional; randomized, double-blind, placebo-controlled[270][271]
Location(s): India
Duration: Jul 2020 – Apr 2021
GX-19[272][273]
Genexine consortium,[274] International Vaccine Institute
DNA Phase I (40)
Location(s): Seoul
Duration: Jun 2020 – Jun 2022
SCB-2019[275][276]
Clover Biopharmaceuticals,[277] GSK
Spike protein trimeric subunit with GSK adjuvant Phase I (150)
Location(s): Perth
Duration: Jun 2020 – Mar 2021
COVAX-19[278]
Vaxine Pty Ltd[279]
Recombinant protein Phase I (40)
Location(s): Adelaide
Duration: Jun 2020 – Jul 2021
Unnamed[280]
PLA Academy of Military Science, Walvax Biotech[281]
mRNA Phase I (168)
Location(s): China
Duration: Jun 2020 – Dec 2021
SARS-CoV-2 Sclamp/V451[282][283]
UQSyneos HealthCEPISeqirus
Molecular clamp stabilized spike protein with MF59 Phase I (120)
Randomised, double-blind, placebo-controlled, dose-ranging
Location(s): Brisbane
Duration: Jul–Oct 2020
N/A N/A
Testing and development terminated in December 2020 due to false positive HIV test found among participants
  1. ^ Latest Phase with published results.
  2. ^ Manufacturing partnership with the National Research Council of Canada and Canadian Center for Vaccinology, Halifax, Nova Scotia[124]
  3. ^ Latest Phase with published results.
  4. ^ Serum Institute of India will be producing the ChAdOx1 nCoV-19 vaccine for India[216] and other low and middle income countries.[217]
  5. ^ Oxford name: ChAdOx1 nCoV-19. Manufacturing in Brazil to be carried out by Oswaldo Cruz Foundation.[218]
  6. ^ Virus-like particles grown in Nicotiana benthamiana[248]
  7. ^ South Korean Phase I–II in parallel with Phase I in the US

Efficacy

Tozinameran (Pfizer-BioNTech COVID-19 vaccine)

The effectiveness of new vaccine is defined by its efficacy.[180] Several COVID-19 vaccines have demonstrated 80+% efficacy in Phase III trials, including mRNA-1273,[284] TozinameranBBIBP-CorV, and Gam-COVID-Vac. In the case of COVID‑19, a vaccine efficacy of 70% may be enough to stop the pandemic. An efficacy of less than 60% may result in failure to create herd immunity.[60][285]

Host-(“vaccinee”)-related determinants that render a person susceptible to infection, such as genetics, health status (underlying disease, nutrition, pregnancy, sensitivities or allergies), immune competence, age, and economic impact or cultural environment can be primary or secondary factors affecting the severity of infection and response to a vaccine.[285] Elderly (above age 60), allergen-hypersensitive, and obese people have susceptibility to compromised immunogenicity, which prevents or inhibits vaccine effectiveness, possibly requiring separate vaccine technologies for these specific populations or repetitive booster vaccinations to limit virus transmission.[285]

In mid-December 2020, a new SARS-CoV-2 variant (VOC-202012/01) was identified in the UK. While preliminary data indicates that this variant showed an estimated increase in reproductive number (R) by 0.4 or greater and an increased transmissibility of up to 70%, there is as yet no evidence for lower vaccine effectiveness.[286]

BCG vaccine

There is experimental evidence that the BCG vaccine has non-specific effects on the immune system, but no evidence that this vaccine is effective against COVID‑19.[287][288]

Use of adjuvants

In September 2020, eleven of the vaccine candidates in clinical development used adjuvants to enhance immunogenicity.[5] An immunological adjuvant is a substance formulated with a vaccine to elevate the immune response to an antigen, such as the COVID‑19 virus or influenza virus.[289] Specifically, an adjuvant may be used in formulating a COVID‑19 vaccine candidate to boost its immunogenicity and efficacy to reduce or prevent COVID-19 infection in vaccinated individuals.[289][290] Adjuvants used in COVID‑19 vaccine formulation may be particularly effective for technologies using the inactivated COVID-19 virus and recombinant protein-based or vector-based vaccines.[290] Aluminum salts, known as “alum”, were the first adjuvant used for licensed vaccines, and are the adjuvant of choice in some 80% of adjuvanted vaccines.[290] The alum adjuvant initiates diverse molecular and cellular mechanisms to enhance immunogenicity, including release of proinflammatory cytokines.[289][290]

Authorizations

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 Ebola epidemic.[291] 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.[291]

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 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 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 the European Medicines Agency (EMA).[292] A rolling review process for the Moderna vaccine candidate was initiated in October by Health Canada and the EMA,[293] and in November in Canada for the Pfizer-BioNTech candidate.[294]

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.[295] 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.[296] In September, the United Arab Emirates approved emergency use of Sinopharm‘s vaccine for healthcare workers,[297] followed by similar emergency use approval from Bahrain in November.[298]

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.”[299] 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.[299] 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.[300][301][302] 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.[303]

The Pfizer-BioNTech partnership submitted an EUA request to the FDA for mRNA Vaccine BNT162b2 (active ingredient tozinameran) on 20 November 2020.[304][305] On 2 December 2020, the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) gave temporary regulatory approval for the Pfizer–BioNTech vaccine,[184]</ref>[306] 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.[183][307][308] 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,[309] as the UK’s vaccination programme began.[310] However, other vaccines had been given earlier in Russia.[311] On 11 December 2020, the US Food and Drug Administration (FDA) granted an Emergency Use Authorization (EUA) for the Pfizer-BioNTech vaccine.[115][312] The vaccine has subsequently been approved for use by a number of national health authorities.[citation needed] On 19 December 2020, the 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, as Swiss laws do not allow emergency approvals.[207][313] On 23 December, a 90-year-old Lucerne resident became the first person to receive the vaccine in continental Europe.[314]

Moderna submitted a request for an EUA for mRNA-1273 to the FDA on 30 November 2020.[315][316] On 18 December 2020, the FDA granted an EUA for the Moderna vaccine.[116][117][118]

Licensure

vaccine licensure occurs after the successful conclusion of the clinical trials program through Phases I–III demonstrating safety, immunogenicity at a specific dose, effectiveness at preventing infection in target populations, and enduring preventive effect.[317] As part of a multinational licensure for a vaccine, the World Health Organization Expert Committee on Biological Standardization developed guidelines of international standards for manufacturing and quality control of vaccines, a process intended as a platform for national regulatory agencies to apply for their own licensure process.[317] Vaccine manufacturers do not receive licensure until a complete clinical package proves the vaccine is safe and has long-term effectiveness, following scientific review by a multinational or national regulatory organization, such as the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA).[318][319]

Upon developing countries adopting WHO guidelines for vaccine development and licensure, each country has its own responsibility to issue a national licensure, and to manage, deploy, and monitor the vaccine throughout its use in each nation.[317] Building trust and acceptance of a licensed vaccine among the public is a task of communication by governments and healthcare personnel to ensure a vaccination campaign proceeds smoothly, saves lives, and enables economic recovery.[320][321] When a vaccine is licensed, it will initially be in limited supply due to variable manufacturing, distribution, and logistical factors, requiring an allocation plan for the limited supply and which population segments should be prioritized to first receive the vaccine.[320]

World Health Organization

Vaccines developed for multinational distribution via the United Nations Children’s Fund (UNICEF) require pre-qualification by the WHO to ensure international standards of quality, safety, immunogenicity, and efficacy for adoption by numerous countries.[317]

The process requires manufacturing consistency at WHO-contracted laboratories following Good Manufacturing Practice (GMP).[317] When UN agencies are involved in vaccine licensure, individual nations collaborate by 1) issuing marketing authorization and a national license for the vaccine, its manufacturers, and distribution partners; and 2) conducting postmarketing surveillance, including records for adverse events after the vaccination program. The WHO works with national agencies to monitor inspections of manufacturing facilities and distributors for compliance with GMP and regulatory oversight.[317]

Some countries choose to buy vaccines licensed by reputable national organizations, such as EMA, FDA, or national agencies in other affluent countries, but such purchases typically are more expensive and may not have distribution resources suitable to local conditions in developing countries.[317]

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, BNT162b2 [mRNA].[322][323] Janssen Cilag Pty Ltd was granted a provisional determination in relation to its COVID-19 vaccine, Ad26.COV2.S, in November 2020.[324]

European Union

In the European Union (EU), vaccines for pandemic pathogens, such as seasonal influenza, are licensed EU-wide where all of the member states comply (“centralized”), are licensed for only some member states (“decentralized”), or are licensed on an individual national level.[318] Generally, all EU states follow regulatory guidance and clinical programs defined by the European Committee for Medicinal Products for Human Use (CHMP), a scientific panel of the European Medicines Agency (EMA) responsible for vaccine licensure.[318] The CHMP is supported by several expert groups who assess and monitor the progress of a vaccine before and after licensure and distribution.[318]

In October 2020, the CHMP started ‘rolling reviews’ of the vaccines known as COVID‑19 Vaccine AstraZeneca (ChAdOx1-SARS-CoV-2) and Pfizer-BioNTech COVID-19 Vaccine (BNT162b2).[325][326][327]

In November 2020, the EMA published a safety monitoring plan and guidance on risk management planning (RMP) for COVID-19 vaccines.[328] 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.[328] All RMPs for COVID-19 vaccines will be published on the EMA’s website.[328] The EMA published guidance for developers of potential COVID-19 vaccines on the clinical evidence to include in marketing authorization applications.[329]

In November 2020, the CHMP started a rolling review of the Moderna vaccine for COVID-19 known as mRNA-1273.[330]

In December 2020, the EMA received application for conditional marketing authorizations (CMA) for the mRNA vaccines BNT162b2 and mRNA1273 (Moderna Covid-19 vaccine).[331][332] The assessments of the vaccines are scheduled to proceed under accelerated timelines with the possibility of opinions issued within weeks.[331][332][333][334]

In December 2020, the CHMP started a rolling review of the Ad26.COV2.S COVID-19 vaccine from Janssen-Cilag International N.V.[237]

On 21 December 2020, the CHMP recommended granting a conditional marketing authorization for tozinameran (Comirnaty), developed by BioNTech and Pfizer.[208][335][111] The recommendation was accepted by the European Commission the same day.[208][336]

United States

Under the FDA, the process of establishing evidence for vaccine clinical safety and efficacy is the same as for the approval process for prescription drugs.[337] If successful through the stages of clinical development, the vaccine licensing process is followed by a Biologics License Application which must provide a scientific review team (from diverse disciplines, such as physicians, statisticians, microbiologists, chemists) a comprehensive documentation for the vaccine candidate having efficacy and safety throughout its development. Also during this stage, the proposed manufacturing facility is examined by expert reviewers for GMP compliance, and the label must have compliant description to enable health care providers definition of vaccine specific use, including its possible risks, to communicate and deliver the vaccine to the public.[337]

The Advisory Committee on Immunization Practices voted on 2 December, that the first doses of the vaccine should be prioritized for health care workers and residents and staff of nursing homes.[338] The board will make guidance who should receive the vaccine next as production increases, which will include older adults, emergency responders, teachers, and essential workers less able to socially distance, and people with comorbidities. However, states will make the final plans for prioritization, distribution, and logistics of vaccinating everyone as supply becomes available.[339] After licensure, monitoring of the vaccine and its production, including periodic inspections for GMP compliance, continue as long as the manufacturer retains its license, which may include additional submissions to the FDA of tests for potency, safety, and purity for each vaccine manufacturing step.[337]

Postmarketing surveillance

Until a vaccine is in use for the general population, all potential adverse events from the vaccine may not be known, requiring manufacturers to conduct Phase IV studies for postmarketing surveillance of the vaccine while it is used widely in the public.[317][337] The WHO works with UN member states to implement postlicensing surveillance.[317] The FDA relies on a Vaccine Adverse Event Reporting System to monitor safety concerns about a vaccine throughout its use in the American public.[337]

Deployment

US airman Ramón Colón-López receives a COVID-19 vaccine at Walter Reed National Military Medical Center in December 2020

As of 26 December 2020, 4.76 million doses of COVID-19 vaccine had been administered worldwide based on official reports from national health agencies.[340]

During a pandemic on the rapid timeline and scale of COVID‑19 infections during 2020, international organizations like the WHO and CEPI, vaccine developers, governments, and industry are evaluating distribution of the eventual vaccine(s).[80] Individual countries producing a vaccine may be persuaded to favor the highest bidder for manufacturing or provide first-service to their own country.[60][52][25] Experts emphasize that licensed vaccines should be available and affordable for people at the frontline of healthcare and having the greatest need.[60][52][25] In April, it was reported that the UK agreed to work with 20 other countries and global organizations including France, Germany and Italy to find a vaccine and to share the results, and that UK citizens would not get preferential access to any new COVID‑19 vaccines developed by taxpayer-funded UK universities.[43] Several companies plan to initially manufacture a vaccine at low cost, then increase costs for profitability later if annual vaccinations are needed and as countries build stock for future needs.[25]

The WHO and CEPI are developing financial resources and guidelines for global deployment of several safe, effective COVID‑19 vaccines, recognizing the need is different across countries and population segments.[5][80][24][98] For example, successful COVID‑19 vaccines would likely be allocated first to healthcare personnel and populations at greatest risk of severe illness and death from COVID‑19 infection, such as the elderly or densely-populated impoverished people.[341][342] The WHO, CEPI, and GAVI have expressed concerns that affluent countries should not receive priority access to the global supply of eventual COVID‑19 vaccines, but rather protecting healthcare personnel and people at high risk of infection are needed to address public health concerns and reduce economic impact of the pandemic.[6][24][341]

Equitable access

Health officials distribute the Moderna COVID-19 vaccine to front line health workers and first responders in Baltimore County, Maryland on December 23, 2020.

During 2020, as the COVID-19 pandemic escalated globally and vaccine development intensified, the WHO COVAX Facility adopted the phrase, “No one is safe unless everyone is safe”, to emphasize the need for equitable distribution of COVID-19 vaccines authorized for marketing.[343] Yet, by mid-December, some 16 countries representing only 14% of the world’s population had preordered more than 10 billion vaccine doses or about 51% of the available world supply.[2][3] Specifically, Canada, Australia, and Japan – having only 1% of the world’s COVID-19 cases – had collectively reserved some one billion vaccine doses,[3] while the COVAX Facility, with a goal to supply vaccines to nearly 100 low-to-middle income countries that cannot fully afford to pay for COVID-19 vaccines, had reserved only a few hundred million doses.[343] Preorders from rich countries were made during 2020 with 13 different vaccine manufacturers, whereas those for low-to-middle income countries were made primarily for the AstraZeneca-Oxford vaccine, which is lowest in cost and has no special refrigeration needs.[2][3]

Due to the high demand of preorders in 2020–21 by wealthy countries, people in developing countries may be excluded from vaccinations until 2023-24 from the first vaccines to be authorized.[3] On 18 December, the COVAX Facility announced it had established agreements with vaccine manufacturers to supply 1.3 billion doses for 92 low-middle income countries in the first half of 2021.[344] To execute its equitable distribution plan in 2021, COVAX remains in an urgent fundraising campaign to raise US$6.8 billion for vaccine purchases and delivery to participating countries in proportion to their populations.[343]

As many of the efforts on vaccine candidates have open-ended outcomes, including a high potential for failure during human testing, CEPI, WHO, and charitable vaccine organizations, such as the Gates Foundation and GAVI, raised over US$20 billion during the first half of 2020, to fund vaccine development and preparedness for vaccinations, particularly for children in under-developed countries.[15][20][53] CEPI had stated that governments should ensure implementation of a globally-fair allocation system for eventual vaccines, using a coordinated system of manufacturing capacity, financing and purchasing, and indemnification from liability to offset risks taken by vaccine developers.[24] Having been created to monitor fair distribution of infectious disease vaccines to low- and middle-income countries,[345][346] CEPI revised its equitable access policy that was published in February to apply to its COVID‑19 vaccine funding: 1) “prices for vaccines will be set as low as possible for territories that are or may be affected by an outbreak of a disease for which CEPI funding was used to develop a vaccine;” 2) “information, know-how and materials related to vaccine development must be shared with (or transferred to) CEPI” so that it can assume responsibility for vaccine development if a company discontinues expenditures for a promising vaccine candidate; 3) CEPI would have access to, and possible management of, intellectual property rights (i.e., patents) for promising vaccines; 4) “CEPI would receive a share of financial benefits that might accrue from CEPI-sponsored vaccine development, to re-invest in support of its mission to provide global public health benefit”; and 5) data transparency among development partners should maintain the WHO Statement on Public Disclosure of Clinical Trial Results, and require results to be published in open-access publications.[346] Some vaccine manufacturers opposed parts of these proposals.[54][346]

International groups, such as the Centre for Artistic Activism and Universities Allied for Essential Medicines, advocate for equitable access to licensed COVID‑19 vaccines.[347][348] Scientists have encouraged that the WHO, CEPI, corporations, and governments collaborate to assure evidence-based allocation of eventual COVID‑19 vaccines determined on infection risk,[345][346] particularly urgent vaccinations provided first for healthcare workers, vulnerable populations, and children.[52][53][54] Similar to the development of the first polio vaccine that was never patented, an effective COVID‑19 vaccine would be available for production and approval by a number of countries and pharmaceutical manufacturing centers worldwide, therefore allowing for a more even and cost-effective distribution on a global scale.[349]

Sovereignty

Favored distribution of vaccines within one or a few select countries, called “vaccine sovereignty”, is a criticism of some of the vaccine development partnerships,[54][345] such as for the AstraZeneca-University of Oxford vaccine candidate, concerning whether there may be prioritized distribution first within the UK and to the “highest bidder” – the United States, which made an advance payment of US$1.2 billion to secure 300 million vaccine doses for Americans, even before the AstraZeneca-Oxford vaccine or a Sanofi vaccine is proved safe or effective.[55][350][351] Concerns exist about whether some countries producing vaccines may impose protectionist controls by export restrictions that would stockpile a COVID‑19 vaccine for their own population.[345]

The Chinese government pledged in May that a successful Chinese vaccine would become a “global, public good”, implying enough doses would be manufactured for both national and global distribution.[352] Unlike mRNA vaccines, which have to be stored at subzero temperatures, inactivated vaccines from Sinovac and Sinopharm require ordinary refrigeration[353] and may have more appeal in developing countries.[354]

In June, the Serum Institute of India (SII) – a major manufacturer of global vaccines – reached a licensing agreement with AstraZeneca to make 1 billion doses of vaccine for low-and-middle income countries;[56] of which half of the doses would go to India.[355] Similar preferential homeland distribution may exist if a vaccine is manufactured in Australia.[356]

Supply chain

Moderna vaccine box packed with insulation and cold packs.

Deploying a COVID-19 vaccine may require worldwide transport and tracking of 10–19 billion vial doses, an effort readily becoming the largest supply chain challenge in history.[60][357][355] As of September 2020, supply chain and logistics experts expressed concern that international and national networks for distributing a licensed vaccine were not ready for the volume and urgency, due mainly to deterioration of resources during 2020 pandemic lockdowns and downsizing that degraded supply capabilities.[357][358][359] Addressing the worldwide challenge faced by coordinating numerous organizations – the COVAX partnership, global pharmaceutical companies, contract vaccine manufacturers, inter- and intranational transport, storage facilities, and health organizations in individual countries – Seth Berkley, chief executive of GAVI, stated: “Delivering billions of doses of vaccine to the entire world efficiently will involve hugely complex logistical and programmatic obstacles all the way along the supply chain.”[360]

As an example highlighting the immensity of the challenge, the International Air Transport Association stated that 8,000 Boeing 747 cargo planes – implemented with equipment for precision vaccine cold storage – would be needed to transport just one dose for people in the more than 200 countries experiencing the COVID‑19 pandemic.[361] GAVI states that “with a fast-moving pandemic, no one is safe, unless everyone is safe.”[341]

In contrast to the multibillion-dollar investment in vaccine technologies and early-stage clinical research, the post-licensing supply chain for a vaccine has not received the same planning, coordination, security or investment.[357][358][362] A major concern is that resources for vaccine distribution in low- to middle-income countries, particularly for vaccinating children, are inadequate or non-existent, but could be improved with cost efficiencies if procurement and distribution were centralized regionally or nationally.[341][363] In September, the COVAX partnership included 172 countries coordinating plans to optimize the supply chain for a COVID‑19 vaccine,[364] and the United Nations Children’s Fund joined with COVAX to prepare the financing and supply chain for vaccinations of children in 92 developing countries.[365][366]

Logistics

Logistics vaccination services assure necessary equipment, staff, and supply of licensed vaccines across international borders.[367] Central logistics include vaccine handling and monitoring, cold chain management, and safety of distribution within the vaccination network.[368] The purpose of the COVAX Facility is to centralize and equitably administer logistics resources among participating countries, merging manufacturing, transport, and overall supply chain infrastructure.[341][362] Included are logistics tools for vaccine forecasting and needs estimation, in-country vaccine management, potential for wastage, and stock management.[368]

Other logistics factors conducted internationally during distribution of a COVID‑19 vaccine may include:[357][369][370]

  • visibility and traceability by barcodes for each vaccine vial
  • sharing of supplier audits
  • sharing of chain of custody for a vaccine vial from manufacturer to the individual being vaccinated
  • use of vaccine temperature monitoring tools
  • temperature stability testing and assurance
  • new packaging and delivery technologies
  • stockpiling
  • coordination of supplies within each country (personal protective equipmentdiluent, syringes, needles, rubber stoppers, refrigeration fuel or power sources, waste-handling, among others)
  • communications technology
  • environmental impacts in each country

A logistics shortage in any one step may derail the whole supply chain, according to one vaccine developer.[371] If the vaccine supply chain fails, the economic and human costs of the pandemic may be extended for years.[359]

Manufacturing capacity

By August 2020, when only a few vaccine candidates were in Phase III trials and were many months away from establishing safety and efficacy, numerous governments pre-ordered more than two billion doses at a cost of more than US$5 billion.[355][371][372] Pre-orders from the British government for 2021 were for five vaccine doses per person, a number dispiriting to organizations like the WHO and GAVI which are promoting fair and equitable access worldwide, especially for developing countries.[355] In September, CEPI was financially supporting basic and clinical research for nine vaccine candidates, with nine more in evaluation, under financing commitments to manufacture two billion doses of three licensed vaccines by the end of 2021.[364] Before 2022, 7–10 billion COVID‑19 vaccine doses may be manufactured worldwide, but the sizable pre-orders by affluent countries – called “vaccine nationalism” – threaten vaccine availability for poorer nations.[60][371][355]

After joining COVAX in October, China initially shared that it would produce 600 million vaccine doses before the end of 2020 and another one billion doses in 2021, although it was unsure how many would be for the country’s own population of 1.4 billion.[373] Sinopharm said it may have the capacity to produce more than 1 billion doses in 2021,[374] while its Dubai partner G42 Healthcare aimed to produce up to 100 million doses in 2021 focused on the middle east.[375] Sinovac aimed to complete a second production facility by the end of 2020 to increase production of CoronaVac to 600 million doses from 300 million,[376] while its Brazilian partner Instituto Butantan planned to produce 100 million doses[377] and its Indonesian partner Bio Farma planned to produce up to 250 million doses of CoronaVac a year.[378]

The Serum Institute of India plans to produce at least one billion vaccine doses, although the institute has stated that half the doses will be used in India.[355]

AstraZeneca CEO, Pascal Soriot, stated: “The challenge is not making the vaccine itself, it’s filling vials. There just aren’t enough vials in the world.”[379] Preparing for high demand in manufacturing vials, an American glass producer invested $163 million in July for a vial factory.[380] Glass availability for vial manufacturing and contaminant control are issues of concern,[381] indicating higher production costs with lower profit potential for developers amid demands for vaccines to be affordable.[341][355][359]

Vaccines must be handled and transported using international regulations, be maintained at controlled temperatures that vary across vaccine technologies, and be used for immunization before deterioration in storage.[355][371] The scale of the COVID‑19 vaccine supply chain is expected to be vast to ensure delivery worldwide to vulnerable populations.[60][358] Priorities for preparing facilities for such distribution include temperature-controlled facilities and equipment, optimizing infrastructure, training immunization staff, and rigorous monitoring.[358][360][365] RFID technologies are being implemented to track and authenticate a vaccine dose from the manufacturer along the entire supply chain to the vaccination.[382]

In September 2020, Grand River Aseptic Manufacturing agreed with Johnson & Johnson to support the manufacture of its vaccine candidate, including technology transfer and fill and finish manufacturing.[383] In October 2020, it was announced that the Moderna vaccine candidate will be manufactured in VispSwitzerland by its partner Lonza Group, which plans to produce the first doses in December 2020.[384] The newly built 2,000-square-metre facility will ramp up production to 300 million doses annually. The ingredient will be shipped frozen at −70 °C to Spain’s Laboratorios Farmacéuticos Rovi SA for the final stage of manufacturing.[384] Lonza’s site in PortsmouthNew Hampshire, aims to start making vaccine ingredients exclusively for the U.S. as early as November.[384]

Cold chain

COVID-19 vaccine shipment protected by thermal wrapping while in transit. (Delta, 16 December 2020)

Vaccines (and adjuvants) are inherently unstable during temperature changes, requiring cold chain management throughout the entire supply chain, typically at temperatures of 2–8 °C (36–46 °F).[370][385] Because COVID‑19 vaccine technologies are varied among several novel technologies, there are new challenges for cold chain management, with some vaccines that are stable while frozen but labile to heat, while others should not be frozen at all, and some are stable across temperatures.[385] Freezing damage and inadequate training of personnel in the local vaccination process are major concerns.[386] If more than one COVID‑19 vaccine is approved, the vaccine cold chain may have to accommodate all these temperature sensitivities across different countries with variable climate conditions and local resources for temperature maintenance.[385] Sinopharm and Sinovac‘s vaccines are examples of inactivated vaccines in Phase III testing which can be transported using existing cold chain systems at 2–8 °C (36–46 °F).[387][388]

modRNA vaccine technologies in development may be more difficult to manufacture at scale and control degradation, requiring ultracold storage and transport.[359] As examples, Moderna’s RNA vaccine candidate requires cold chain management just above freezing temperatures between 2 and 8 °C (36 and 46 °F) with limited storage duration (30 days),[389] but the Pfizer-BioNTech RNA candidate requires storage between −80 and −60 °C (−112 and −76 °F),[94] or colder throughout deployment until vaccination.[390][391]

After a vaccine vial is punctured to administer a dose, it is viable for only six hours, then must be discarded, requiring attention to local management of cold storage and vaccination processes.[60][392] Because the COVID‑19 vaccine will likely be in short supply for many locations during early deployment, vaccination staff will have to avoid spoilage and waste, which typically are as much as 30% of the supply.[357][392] The cold chain is further challenged by the type of local transportation for the vaccines in rural communities, such as by motorcycle or delivery drone, need for booster doses, use of diluents, and access to vulnerable populations, such as healthcare staff, children and the elderly.[60][365][393]

Air and land transport

Coordination of international air cargo is an essential component of time- and temperature-sensitive distribution of COVID‑19 vaccines, but, as of September 2020, the air freight network is not prepared for multinational deployment.[358][361][394] “Safely delivering COVID‑19 vaccines will be the mission of the century for the global air cargo industry. But it won’t happen without careful advance planning. And the time for that is now. We urge governments to take the lead in facilitating cooperation across the logistics chain so that the facilities, security arrangements and border processes are ready for the mammoth and complex task ahead,” said IATA’s Director General and CEO, Alexandre de Juniac, in September 2020.[394]

For the severe reduction in passenger air traffic during 2020, airlines downsized personnel, trimmed destination networks, and put aircraft into long-term storage.[358][394] As the lead agencies for procurement and supply of the COVID-19 vaccine within the WHO COVAX Facility, GAVI and UNICEF are preparing for the largest and fastest vaccine deployment ever, necessitating international air freight collaboration, customs and border control, and possibly as many as 8,000 cargo planes to deliver just one vaccine dose to multiple countries.[365][394]

Two of the first approved vaccines, Pfizer and BioNTech’s Pfizer-BioNTech COVID-19 vaccine and Moderna’s mRNA-1273, must be kept cold during transport. Keeping the temperatures sufficiently low is accomplished with specially-designed containers[a] and dry ice, but dry ice is only allowed in limited quantities on airplanes as the gases released via sublimation may be toxic. In the United States, the Federal Aviation Administration (FAA) limits the amount of dry ice on a Boeing 777-224 to 3,000 lb (1,400 kg), but it temporarily allowed United Airlines to transport up to 15,000 lb (6,800 kg)—nearly 1 million doses—between Brussels and Chicago. The CDC has tasked McKesson with vaccine distribution in the US; the company will handle all major vaccines except Pfizer’s. American AirlinesBoeing, and Delta Airlines are also working to increase dry ice transportation capacity, and American, Delta, and United each operate their own cold storage networks in the US. FedEx and UPS have installed ultra-cold freezers at air cargo hubs in Europe and North America, and UPS can manufacture 1,200 lb (540 kg) of dry ice per hour.[397]

Security and corruption

Medicines are the world’s largest fraud market, worth some $200 billion per year, making the widespread demand for a COVID-19 vaccine vulnerable to counterfeit, theft, scams, and cyberattacks throughout the supply chain.[362][398] The vaccine has been referred to as “the most valuable asset on earth”; Interpol called it “liquid gold” and warned of an “onslaught of all types of criminal activity”.[399] Anticorruption, transparency, and accountability safeguards are being established to reduce and eliminate corruption of COVID‑19 vaccine supplies.[398][400] Absence of harmonized regulatory frameworks among countries, including low technical capacity, constrained access, and ineffective capability to identify and track genuine vs. counterfeit vaccines, may be life-threatening for vaccine recipients, and would potentially perpetuate the COVID‑19 pandemic.[398] Tracking system technologies for packaging are being used by manufacturers to trace vaccine vials across the supply chain,[362] and to use digital and biometric tools to assure security for vaccination teams.[382][401] In December 2020, Interpol warned that organized crime could infiltrate the vaccine supply chain, steal product through physical means, and data theft, or even offer counterfeit vaccine kits.[402] Further, vaccines which require constant freezing temperatures are also susceptible to sabotage.[399]

GPS devices will be used in the United States to track the vaccines. In Colorado, the vaccine shipments will be escorted by Colorado State Patrol officers from Denver International Airport to the state’s eight distribution points; the exact plans are confidential and law enforcement will “maintain a low-key profile”.[396]

Peripheral businesses may also be affected. An IBM security analyst told The New York Times that petrochemical companies are being targeted by hackers due to their central role in producing dry ice.[399]

National infrastructure

The WHO has implemented an “Effective Vaccine Management” system,[403] which includes constructing priorities to prepare national and subnational personnel and facilities for vaccine distribution, including:

  • Trained staff to handle time- and temperature-sensitive vaccines
  • Robust monitoring capabilities to ensure optimal vaccine storage and transport
  • Temperature-controlled facilities and equipment
  • Traceability
  • Security

Border processes for efficient handling and customs clearance within individual countries may include:[367][403]

  • Facilitating flight and landing permits
  • Exempting flight crews from quarantine requirements
  • Facilitating flexible operations for efficient national deployment
  • Granting arrival priority to maintain vaccine temperature requirements

Liability

On 4 February 2020, US Secretary of Health and Human Services Alex Azar published a notice of declaration under the Public Readiness and Emergency Preparedness Act for medical countermeasures against COVID‑19, covering “any vaccine, used to treat, diagnose, cure, prevent, or mitigate COVID‑19, or the transmission of SARS-CoV-2 or a virus mutating therefrom”, and stating that the declaration precludes “liability claims alleging negligence by a manufacturer in creating a vaccine, or negligence by a health care provider in prescribing the wrong dose, absent willful misconduct”.[404] The declaration is effective in the United States through 1 October 2024.[404]

Society and culture

Misinformation

Social media posts have previously promoted a conspiracy theory that a COVID‑19 vaccine was already available when it was not. The patents cited by these various social media posts had references to existing patents for genetic sequences and vaccines for other strains such as the SARS coronavirus, but not for COVID‑19.[405][406]

On 21 May 2020, the FDA made public the cease-and-desist notice it had sent to North Coast Biologics, a Seattle-based company that had been selling a purported “nCoV19 spike protein vaccine”.[407]

Vaccine hesitancy

Some 10% of the public perceives vaccines as unsafe or unnecessary, refusing vaccination – a global health threat called vaccine hesitancy[408] – which increases the risk of further viral spread that could lead to COVID‑19 outbreaks.[100] In mid-2020, estimates from two surveys were that 67% or 80% of people in the U.S. would accept a new vaccination against COVID‑19, with wide disparity by education level, employment status, race, and geography.[300][409]

A poll conducted by National Geographic and Morning Consult demonstrated a gender gap on willingness to take a COVID-19 vaccine in the U.S., with 69% of men polled saying they would take the vaccine, compared to only 51% of women. The poll also showed a positive correlation between education level and willingness to take the vaccine.[410]

Lack of public data and trust

The United Arab Emirates’ announcement of the approval for the Chinese vaccine BBIBP-CorV noticeably lacked data and other critical details.[411] Unlike vaccines being developed in some Western countries, there is little public information about Chinese vaccines’ safety or efficacy.[412] While the UAE said it had reviewed Sinopharm’s interim data analysis, there was no indication it had independently analyzed the raw data. It is unclear how Sinopharm drew conclusions from the data, since the UAE did not state critical details of the analysis, such as the number of COVID-19 cases or the volunteers’ ages. [411] Zhengming Chen, a University of Oxford epidemiologist, said, “It’s difficult to tell how well the vaccine works. I hope it is real.”[413]

The lack of public data could limit Sinopharm from sending the vaccine to a variety of other countries, as confidence in BBIBP-CorV’s safety and efficacy will be crucial to its successful rollout internationally. Chen said that to convince other countries to follow suit requires solid scientific evidence and robust data that are open to scrutiny. Jin Dong-Yan, a virologist at the University of Hong Kong, was concerned that countries might have to decide whether to accept the vaccine without independent analysis or not to use it at all.[413]

There is a similar dispute regarding CoronaVac, another Chinese vaccine. On December 14, 2020, Anvisa, the Brazilian Health Regulatory Agency, said emergency use authorization is not yet public in China. Anvisa said there is no information available on the criteria used by Chinese authorities when CoronaVac was granted permission for emergency use in China in June 2020.[414] On December 23, 2020, researchers in Brazil said the vaccine was more than 50% effective in the trial, but withheld full results at Sinovac’s request, raising questions again about transparency.[415]

In an effort to demonstrate the vaccine’s safety, prominent politicians have received it on camera, with others pledging to do so.[416][417][418]