COVID-19 Vaccine

A **COVID‑19 vaccine** is a vaccine intended to provide acquired immunity against COVID-19. Prior to the COVID-19 pandemic, work to develop a vaccine against 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 seven vaccines for public use: two RNA vaccines (the Pfizer-BioNTech COVID-19 vaccine and mRNA-1273 from Moderna), three conventional inactivated vaccines (BBIBP-CorV from Sinopharm, BBV152 from Bharat Biotech and CoronaVac from Sinovac), and two viral vector vaccines (Gam-COVID-Vac from the Gamaleya Research Institute and AZD1222 from the University of Oxford and AstraZeneca).

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.[2] As of 14 January 2021, 32.64 million doses of COVID-19 vaccine had been administered worldwide based on official reports from national health agencies.[3] 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,[4] with about half of the doses purchased by high-income countries comprising only 14% of the world's population.[5]

## Planning and investment

Since early 2020, vaccine development has been expedited via unprecedented collaboration in the multinational pharmaceutical industry and between governments.[6] 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.[6][7]

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.[8][9] For comparison, during the 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 Phase II–III trials of about US$1 billion.[8]

### International organizations

#### Access to COVID-19 Tools (ACT) Accelerator

Main article: Access to COVID-19 Tools Accelerator

The Access to COVID-19 Tools Accelerator (ACT Accelerator), or the *Global Collaboration to Accelerate the Development, Production and Equitable Access to New COVID-19 diagnostics, therapeutics and vaccines*, is a G20 initiative announced by pro-tem Chair Mohammed al-Jadaan on 24 April 2020.[10] A call to action was published simultaneously by the World Health Organization (WHO) on 24 April.[11]

On 10 September, the UN and European Union cohosted the Inaugural Meeting of the Facilitation Council of the ACT-Accelerator, which had received $2.7 billion of the $35 billion necessary to secure the 2 billion COVID-19 vaccine doses, 245 million treatments, and 500 million tests that the initiative deemed necessary to shorten the pandemic and speed economic global recovery.[12] Sir Andrew Witty and Dr Ngozi Okonjo-Iweala have accepted to act as Special Envoys to the ACT Accelerator from the WHO.[13] During the Trump administration, the United States withdrew its financial support of the WHO, and did not support the ACT Accelerator.[14]

The ACT Accelerator is a cross-discipline support structure to enable partners to share resources and knowledge. It comprises four pillars, each managed by two to three collaborating partners:[15]

* Vaccines (also called "COVAX")
* Diagnostics
* Therapeutics
* Health Systems Connector

##### Vaccines 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".[17][18] 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.[19][20]
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.[21] 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.[21]

##### Financial contributions

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.[22][23] See table above.[24]

Earlier in 2020, the WHO had a telethon which raised US$8.8 billion in pledges from forty countries to support rapid development of vaccines.[25] 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.[26][27]
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.[28]

##### Coalition for Epidemic Preparedness Innovations

Further information: 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.[20] 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.[21][22][29] The United Kingdom, Canada, Belgium, Norway, Switzerland, Germany and the Netherlands had already donated US$915 million to CEPI by early May.[25][30] 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.[31][32]
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.[22][33] As of December, the vaccine research organizations and programs being supported by CEPI were AstraZeneca/University of Oxford (AZD1222), Clover Biopharmaceuticals (SCB-2019), CureVac (Zorecimeran/CVnCoV), Inovio (INO-4800), Institut Pasteur (MV-SARS-CoV-2), Moderna (mRNA-1273), Novavax (NVX-CoV2373), SK bioscience (GBP510), and Hong Kong University.[22][34][35]

### National governments

Governments dedicating resources for national or international investments in vaccine research, development, and manufacturing beginning in 2020 included:

* Canada: Announced CA$275 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.[36][37] A further investment of CA$1.1 billion was added to support clinical trials and develop manufacturing and supply chains for vaccines.[38] 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.[39]

* China: Provided low-rate loans to a vaccine developer through its central bank and "quickly made land available for the company" to build production plants.[40] As of June 2020, six of the eleven COVID‑19 vaccine candidates in early-stage human testing were developed by Chinese organizations.[41] 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.[42] On 18 May, China had pledged US$2 billion to support overall efforts by the WHO for programs against COVID‑19.[43] On 22 July, China announced plans to provide a US$1 billion loan to make its vaccine accessible for Latin America and the Caribbean.[44] On 24 August, Chinese Premier Li Keqiang announced it would provide Cambodia, Laos, Myanmar, Thailand, and Vietnam priority access to the vaccine once it was distributed.[45]

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.[46] The vaccine development initiatives at the University of Oxford and Imperial College of London were financed with GB£44 million.[47][48]
* United States: The Biomedical Advanced Research and Development Authority (BARDA), a federal agency funding disease-fighting technology, announced investments of nearly US$1 billion to support American COVID‑19 vaccine development and manufacture of the most promising candidates. On 16 April, BARDA made a US$483 million investment in vaccine developer Moderna and its partner, Johnson & Johnson.[40][49] BARDA has earmarked an additional US$4 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.[49][50] 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 300 million doses of a licensed vaccine by January 2021. The project's chief advisor is Moncef Slaoui and its chief operating officer is General Gustave Perna.[51][52] In June, the Warp Speed team said it would work with seven companies developing vaccine candidates: Moderna, Johnson & Johnson, Merck, Pfizer, the University of Oxford in collaboration with AstraZeneca, and two others,[53] although Pfizer later stated that "all the investment for R&D was made by Pfizer at risk."[54]

#### Donations to Access to COVID-19 Tools (ACT) Accelerator

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 (Vienna, Austria), and the University of Pittsburgh, bringing CEPI's total investment in COVID‑19 vaccine development to US$480 million by May.[55][56] Belgium, Norway, Switzerland, Germany, and the Netherlands have been major contributors to the CEPI effort for COVID‑19 vaccine research in Europe.[30]
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.[57] On 18 May, China had pledged US$2 billion to support overall efforts by the WHO for programs against COVID‑19.[58] 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.[59] 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.[30]

### 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.[40][41] 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.[60]

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.[61][62][63][64] 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.[61][41][63] 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.[64] AstraZeneca stated that initial pricing of its vaccine would not include a profit margin for the company while the pandemic was still expanding.[64]

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.[65] 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.[61][40][41][62] Pfizer indicated it was not interested in a government partnership, considering it to be a "third party" slowing progress.[66] 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.[66]

## Development

### Background

Prior to COVID-19, a vaccine for an infectious disease had never been produced in less than several years--and no vaccine existed for preventing a coronavirus infection in humans.[67] 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.[68] 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[69] and MERS[70] 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.[71][72][73] As of 2020, there is no cure or protective vaccine proven to be safe and effective against SARS in humans.[74][75]

There is also no proven vaccine against MERS.[76] 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.[74][77] As of March 2020, there was one (DNA based) MERS vaccine which completed Phase I clinical trials in humans[78] and three others in progress, all being viral-vectored vaccines: two adenoviral-vectored (ChAdOx1-MERS, BVRS-GamVac) and one MVA-vectored (MVA-MERS-S).[79]

### Early development

NIAID (NIH) scientist researching COVID-19 vaccine examines agar plate. (30 January 2020)

After a coronavirus was isolated in December 2019,[80] its 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.[7][61][81]

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.[82] 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,[83] with four vaccine candidates entering human evaluation in March (see the table of clinical trials started in 2020, below).[7][84]

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.[83]

By April 2020, "almost 80 companies and institutes in 19 countries" were working on this virtual gold rush.[85] 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.[6][84][67] Another analysis estimates ten candidates will need simultaneous initial development, before a select few are chosen for the final path to licensing.[67]

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.[86]

### Compressed timelines

The urgency to create a vaccine for COVID-19, led to compressed schedules that shortened the standard vaccine development timeline, in some cases combining clinical trial steps over months, a process typically conducted sequentially over years.[41] 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.[67][87] 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.[40][41] As an example, Chinese vaccine developers and the government Chinese Center for Disease Control and Prevention began their efforts in January 2020,[88] 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.[41][89]

### Preclinical research

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.[90] 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.[7]

Industry analysis of past vaccine development shows failure rates of 84–90%.[7][91] 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.[7]

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.[7] 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.[6]

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.[6][7]

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%.[8]

### 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.[6] 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.[6] Platforms being developed in 2020 involved nucleic acid technologies (nucleoside-modified messenger RNA and DNA), non-replicating viral vectors, peptides, recombinant proteins, live attenuated viruses, and inactivated viruses.[67][7][6][92]

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.[7][6][92] 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.[7][6]

### 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.[92][7][94] 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,[91] and CEPI indicates a potential success rate of only 10% for vaccine candidates in 2020 development.[7]

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."[7]

Research at universities is obstructed by physical distancing and closing of laboratories.[95][96]

#### 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-level 3 containment measures for handling live viruses, and international coordination to ensure standardized safety procedures.[92][7]

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.[92][97] 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.[92][97] The antibody response to a vaccine is a variable of vaccine technologies in development, including whether the vaccine has precision in its mechanism,[92] and choice of the route for how it is given (intramuscular, intradermal, oral, or nasal).[97]

#### 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.[98] 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.[67][61][41] There was a possibility that billions of dollars could be invested without success.[40]

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.[99] From Phase I clinical trials, 84–90%[7][91] of vaccine candidates fail to make it to final approval during development, and from Phase III, 25.7% fail[91] – the investment by a manufacturer in a vaccine candidate may exceed US$1 billion and end with millions of useless doses given advanced manufacturing agreements.[67][40][41]

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.[100] In December 2020, a Belgian politician briefly published the confidential prices agreed between vaccine producers and the EU:[101]

 Johnson&Johnson
 Sanofi/GSK
 Pfizer/BioNTech
 CureVac
 Moderna

#### Supply of raw materials

Globally, supplies critical to vaccine research and development are increasingly scarce due to international competition or national sequestration.[103]

#### Rollout

See also: COVID-19 vaccination programme in the United Kingdom

Different vaccines have different shipping and handling requirements. For example, the Pfizer-BioNTech COVID-19 vaccine must be shipped and stored between −80 and −60 °C (−112 and −76 °F),[104] must be used within five days of thawing,[104] and has a minimum order of 975 doses, making it unlikely to be rolled out in settings other than large, well-equipped hospitals.[105] The Moderna vaccine vials require storage above −40 °C (−40 °F) and between −25 and −15 °C (−13 and 5 °F).[106] Once refrigerated, the Moderna vaccine can be kept between 2 and 8 °C (36 and 46 °F) for up to 30 days.[106]

### 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.[83] 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;[107] 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[83][108] – 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.[83] 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.[83]

#### 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.[109] 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.[109] 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.[109] In addition to competition over recruiting participants, clinical trial organizers may encounter people unwilling to be vaccinated due to vaccine hesitancy[110] or disbelieving the science of the vaccine technology and its ability to prevent infection.[111]

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.[109][112]

#### 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.[113][114] 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.[108] 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.[108]

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.[108][113]

#### Proposed challenge studies

Main article: 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.[115][116][117][118] 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.[116][117] Challenge studies have been used for diseases less deadly than COVID‑19 infection, such as common influenza, typhoid fever, cholera, and malaria.[117][118] 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.[119] 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.[120] 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.[120]

## Vaccines development status

As of 21 December, many countries and the European Union[121] 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 Sinopharm.[122][123] 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 UK vaccination programme.[124] 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.[125] A week later, they granted an EUA for mRNA-1273, the Moderna vaccine.[126][127][128]

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.[6] 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.[6]

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.[129][130] A Phase I–II trial consists of preliminary safety and immunogenicity testing, is typically randomized, placebo-controlled, while determining more precise, effective doses.[130] 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.[129][130] 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.[109][131][132]

### Vaccine candidates

1. **^** Latest Phase with published results.
2. ^ Jump up to:***a*** ***b*** US authorization also includes the three sovereign nations in the Compact of Free Association: Palau, the Marshall Islands, and Micronesia.[164][165]
3. **^** Serum Institute of India will be producing the *ChAdOx1 nCoV-19* vaccine for India[201] and other low and middle income countries.[202]
4. **^** Oxford name: *ChAdOx1 nCoV-19*. Manufacturing in Brazil to be carried out by Oswaldo Cruz Foundation.[203]
5. **^** Latest Phase with published results.
6. **^** Virus-like particles grown in *Nicotiana benthamiana*[312]
7. **^** South Korean Phase I–II in parallel with Phase I in the US

### Efficacy

See also: Vaccine efficacy

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)[350]

The effectiveness of a new vaccine is defined by its efficacy.[140] In the case of COVID‑19, a vaccine efficacy of 67% may be enough to slow the pandemic, but this assumes that the vaccine confers sterilizing immunity, which is necessary to prevent transmission. Vaccine efficacy reflects disease prevention, a poor indicator of transmissibility of SARS-CoV-2 since asymptomatic people can be highly infectious.[351] The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have set a cut-off of 50% as the efficacy required to approve a COVID-19 vaccine.[352][353] As of 7 January, authorized and approved vaccines have shown efficacies ranging from 62%-90% for AZD1222 (various dosage regimens) to 95% for the Pfizer-BioNTech COVID-19 vaccine.[*medical citation needed*] BBV152 has not published efficacy results as of 7 January.[354]

With BBIBP-CorV, Sinopharm announced a vaccine's efficacy was 79.34%, which was lower than the 86% announced by the United Arab Emirates (UAE) on 9 December. The UAE based its results on an interim analysis of Phase III trials conducted from July.[355] 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.[356]

With CoronaVac, after three delays in releasing results,[357] Instituto Butantan announced in January 2021 that the vaccine was 78% effective in mild cases and 100% effective against severe and moderate infections based on 220 COVID-19 cases from 13,000 volunteers. Butantan declined to elaborate how the efficacy rate was calculated.[358] Previously, in late December 2020, Butantan said the vaccine is between 50% and 90% effective in Brazil, but withheld full results at Sinovac's request.[357][359] Separately on 24 December, Turkey released Phase III results from an interim analysis of 29 cases which showed an efficacy rate of 91.25% based on the data of 1,322 participants in a trial involving 7,371 volunteers, a confusing readout compared to Brazil.[360][361][359]

#### SARS-CoV-2 variant

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.[362]

### BCG vaccine

Scientists investigated whether existing vaccines for unrelated conditions could prime the immune system and lessen the severity of COVID-19 infection.[363] There is experimental evidence that the BCG vaccine for tuberculosis has non-specific effects on the immune system, but no evidence that this vaccine is effective against COVID‑19.[364][365]

### Use of adjuvants

As of September 2020, eleven of the vaccine candidates in clinical development use adjuvants to enhance immunogenicity.[6] 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.[366] 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.[366][367] 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.[367] 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.[367] The alum adjuvant initiates diverse molecular and cellular mechanisms to enhance immunogenicity, including release of proinflammatory cytokines.[366][367]

### Smart patch

On 6 January 2021 it was announced that the first coronavirus vaccine "smart patch" was being developed at Swansea University in Wales. The disposable device will use micro-needles to both administer the vaccine and to monitor its efficacy by measuring the body's immune response.

A prototype would be developed by the end of March, anticipating possible clinical trials. Researchers aimed to make the device commercially available within three years. The project received Welsh Government and European funding as part of the global response to the COVID pandemic, although it was also hoped it could be used to treat other infectious diseases.[368]

## 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.[369] 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.[369]

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 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).[370] A rolling review process for the Moderna vaccine candidate was initiated in October by Health Canada and the EMA,[371] and in November in Canada for the Pfizer-BioNTech candidate.[372]

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.[373] 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.[374] In September, the United Arab Emirates approved emergency use of Sinopharm's vaccine for healthcare workers,[375] followed by similar emergency use approval from Bahrain in November.[376]

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."[377] 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.[377] 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.[378][379][380] 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.[381]

The Pfizer-BioNTech partnership submitted an EUA request to the FDA for the mRNA vaccine BNT162b2 (active ingredient tozinameran) on 20 November 2020.[382][383] On 2 December 2020, the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) gave temporary regulatory approval for the Pfizer–BioNTech vaccine,[162][384] 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.[161][385][386] 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,[387] as the UK's vaccination programme began.[388] However, other vaccines had been given earlier in Russia.[389] On 11 December 2020, the US Food and Drug Administration (FDA) granted an Emergency Use Authorization (EUA) for the Pfizer-BioNTech vaccine.[125][390] 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.[179][391] On 23 December, a 90-year-old Lucerne resident became the first person to receive the vaccine in continental Europe.[392]

Moderna submitted a request for an EUA for mRNA-1273 to the FDA on 30 November 2020.[393][394] On 18 December 2020, the FDA granted an EUA for the Moderna vaccine.[126][127][128]

The UK's regulator (MHRA) gave the first approval to the Oxford/AstraZeneca vaccine on 30 December 2020, as their second vaccine to enter the national rollout.[395]

## Licensure

A *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.[396] 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.[396] 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).[397][398]

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.[396] 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.[399][400] 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.[399]

### 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.[396]

The process requires manufacturing consistency at WHO-contracted laboratories following Good Manufacturing Practice (GMP).[396] 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.[396]

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.[396]

### 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].[401][402] Janssen Cilag Pty Ltd was granted a provisional determination in relation to its COVID-19 vaccine, Ad26.COV2.S, in November 2020.[403]

### 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.[397] 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.[397] The CHMP is supported by several expert groups who assess and monitor the progress of a vaccine before and after licensure and distribution.[397]

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).[404][405][406] 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.[407]

In November 2020, the EMA published a safety monitoring plan and guidance on risk management planning (RMP) for COVID-19 vaccines.[408] 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.[408] All RMPs for COVID-19 vaccines will be published on the EMA's website.[408] The EMA published guidance for developers of potential COVID-19 vaccines on the clinical evidence to include in marketing authorization applications.[409]

In November 2020, the CHMP started a rolling review of the Moderna vaccine for COVID-19 known as mRNA-1273.[410]

In December 2020, the EMA received application for conditional marketing authorizations (CMA) for the mRNA vaccines *BNT162b2* and *mRNA1273* (*Moderna Covid-19 vaccine*).[411][412] The assessments of the vaccines are scheduled to proceed under accelerated timelines with the possibility of opinions issued within weeks.[411][412][413][414]

In December 2020, the CHMP started a rolling review of the Ad26.COV2.S COVID-19 vaccine from Janssen-Cilag International N.V.[292]

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.[415][416][121] The recommendation was accepted by the European Commission the same day.[415][417]

In January 2021, the EMA received an application for conditional marketing authorization (CMA) for the COVID-19 vaccine known as *COVID-19 Vaccine AstraZeneca*, developed by AstraZeneca and Oxford University.[418]

### 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.[419] 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.[419] 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.[419]

### 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.[396][419] The WHO works with UN member states to implement postlicensing surveillance.[396] The FDA relies on a Vaccine Adverse Event Reporting System to monitor safety concerns about a vaccine throughout its use in the American public.[419]

As of 15 January 2021, 35.3 million doses of COVID-19 vaccine had been administered worldwide based on official reports from national health agencies.[3]

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).[83] Individual countries producing a vaccine may be persuaded to favor the highest bidder for manufacturing or provide first-service to their own country.[67][61][40] Experts emphasize that licensed vaccines should be available and affordable for people at the frontline of healthcare and having the greatest need.[67][61][40] 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.[47] 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.[40]

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.[6][83][84][108] 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.[421][422] 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.[7][84][421]

### Phased distribution

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.[2]

In the United States, the CDC's Advisory Committee on Immunization Practices (ACIP) voted on 1 December that the first doses of the vaccine should be prioritized for healthcare workers and residents and staff of nursing homes.[423] ACIP recommended that the second phase of distribution (Phase 1b) include persons aged ≥75 years and non-healthcare frontline essential workers.[424] However, states control the final plans for prioritization, distribution, and logistics of vaccinating everyone as supply becomes available.[425]

The European Union began phased vaccine rollout on 27 December. Each member state is managing distribution with a common focus on prioritizing healthcare workers, people at high risk of exposure, the elderly, and those with serious health conditions.[426][427]

The COVID-19 vaccination program in the United Kingdom prioritized elder care facility residents and carers, followed by healthcare workers and those over 80 years of age. Subsequent phases are based largely on age, declining from 75 years in 5-year increments.[428]

### Equitable access

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.[429] 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.[4][5] Specifically, Canada, Australia, and Japan – having only 1% of the world's COVID-19 cases – had collectively reserved some one billion vaccine doses,[5] 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.[429] 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.[4][5]

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.[5] 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.[430] 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.[429]

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.[431][432][62] 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.[84] Having been created to monitor fair distribution of infectious disease vaccines to low- and middle-income countries,[433][434] 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.[434] Some vaccine manufacturers opposed parts of these proposals.[63][434]

International groups, such as the Centre for Artistic Activism and Universities Allied for Essential Medicines, advocate for equitable access to licensed COVID‑19 vaccines.[435][436] 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,[433][434] particularly urgent vaccinations provided first for healthcare workers, vulnerable populations, and children.[61][62][63] 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.[437]

In the initial period of availability, states have prioritized certain groups such as health workers or the elderly to be vaccinated. However, since the Moderna and Pfizer-BioNTech vaccines have a validity of hours after being prepared for administration, ready doses may remain after the day's scheduled persons have been vaccinated (due to last-moment rejection or illness). Due to the scarcity of the vaccine, these doses should be applied rather than discarded. This case may lead to improvisation with ensuing criticism on the choices made.[438]

### 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,[63][433] 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 was proved safe or effective.[64][439][440] 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.[433]

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.[441] Unlike mRNA vaccines, which have to be stored at subzero temperatures, inactivated vaccines from Sinovac and Sinopharm require ordinary refrigeration[442] and may have more appeal in developing countries.[443]

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,[65] of which half of the doses would go to India.[444] Similar preferential homeland distribution may exist if a vaccine is manufactured in Australia.[445]

## 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.[67][446][444] 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.[446][447][448] 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."[449]

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.[450] GAVI states that "with a fast-moving pandemic, no one is safe, unless everyone is safe."[421]

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.[446][447][451] 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.[421][452] In September, the COVAX partnership included 172 countries coordinating plans to optimize the supply chain for a COVID‑19 vaccine,[453] 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.[454][455]

### Logistics

Logistics vaccination services assure necessary equipment, staff, and supply of licensed vaccines across international borders.[456] Central logistics include vaccine handling and monitoring, cold chain management, and safety of distribution within the vaccination network.[457] 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.[421][451] Included are logistics tools for vaccine forecasting and needs estimation, in-country vaccine management, potential for wastage, and stock management.[457]

Other logistics factors conducted internationally during distribution of a COVID‑19 vaccine may include:[446][458][459]

* 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 equipment, diluent, 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.[460] If the vaccine supply chain fails, the economic and human costs of the pandemic may be extended for years.[448]

### 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.[444][460][461] 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.[444] 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.[453] 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.[67][460][444]

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.[462] Sinopharm said it may have the capacity to produce more than 1 billion doses in 2021,[463] while its Dubai partner G42 Healthcare aimed to produce up to 100 million doses in 2021 focused on the middle east.[464] 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,[465] while its Brazilian partner Instituto Butantan planned to produce 100 million doses[466] and its Indonesian partner Bio Farma planned to produce up to 250 million doses of CoronaVac a year.[467]

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.[444]

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."[468] Preparing for high demand in manufacturing vials, an American glass producer invested $163 million in July for a vial factory.[469] Glass availability for vial manufacturing and contaminant control are issues of concern,[470] indicating higher production costs with lower profit potential for developers amid demands for vaccines to be affordable.[421][444][448]

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.[444][460] The scale of the COVID‑19 vaccine supply chain is expected to be vast to ensure delivery worldwide to vulnerable populations.[67][447] Priorities for preparing facilities for such distribution include temperature-controlled facilities and equipment, optimizing infrastructure, training immunization staff, and rigorous monitoring.[447][449][454] RFID technologies are being implemented to track and authenticate a vaccine dose from the manufacturer along the entire supply chain to the vaccination.[471]

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.[472] In October 2020, it was announced that the Moderna vaccine candidate will be manufactured in Visp, Switzerland by its partner Lonza Group, which plans to produce the first doses in December 2020.[473] 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.[473] Lonza's site in Portsmouth, New Hampshire, aims to start making vaccine ingredients exclusively for the U.S. as early as November.[473]

### Cold chain

See also: ULT freezer

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).[459][474] 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.[474] Freezing damage and inadequate training of personnel in the local vaccination process are major concerns.[475] 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.[474] 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).[476][477]

modRNA vaccine technologies in development may be more difficult to manufacture at scale and control degradation, requiring ultracold storage and transport.[448] 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),[478] but the Pfizer-BioNTech RNA candidate requires storage between −80 and −60 °C (−112 and −76 °F),[104] or colder throughout deployment until vaccination.[479][480]

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.[67][481] 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.[446][481] 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.[67][454][482]

### 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.[447][450][483] "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.[483]

For the severe reduction in passenger air traffic during 2020, airlines downsized personnel, trimmed destination networks, and put aircraft into long-term storage.[447][483] 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.[454][483]

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 Airlines, Boeing, 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.[486]

### 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.[451][487] 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".[488] Anticorruption, transparency, and accountability safeguards are being established to reduce and eliminate corruption of COVID‑19 vaccine supplies.[487][489] 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.[487] Tracking system technologies for packaging are being used by manufacturers to trace vaccine vials across the supply chain,[451] and to use digital and biometric tools to assure security for vaccination teams.[471][490] 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.[491] Further, vaccines which require constant freezing temperatures are also susceptible to sabotage.[488]

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".[485]

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.[488]

### National infrastructure

The WHO has implemented an "Effective Vaccine Management" system,[492] 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:[456][492]

* 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".[493] The declaration is effective in the United States through 1 October 2024.[493]

In the European Union the COVID‑19 vaccines are licensed under a Conditional Marketing Authorisation which does not exempt manufacturers from civil and administrative liability claims.[494] While the purchasing contracts with vaccine manufacturers remain secret, they do not contain liability exemptions even for side-effects not known at the time of licensure.[495]

## Society and culture

### Misinformation

Main article: Misinformation related to the COVID-19 pandemic § Vaccine 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.[496][497]

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".[498]

### Vaccine hesitancy

Some 10% of the public perceives vaccines as unsafe or unnecessary, refusing vaccination – a global health threat called vaccine hesitancy[499] – which increases the risk of further viral spread that could lead to COVID‑19 outbreaks.[110] 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.[378][500]

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.[501]

### Lack of public trust

In an effort to demonstrate the vaccine's safety, prominent politicians have received it on camera, with others pledging to do so.[502][503][504]

### Brand names

The vaccine manufacturers are awaiting full approvals to name their vaccines.[505][506]