COVID-19 vaccine

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A COVID‑19 vaccine is a biotechnology product intended to provide acquired immunity against coronavirus disease 2019 (COVID‑19). As of September 2020, there were 321 vaccine candidates in development, a 2.5 fold increase since April. However, no candidate has completed clinical trials to prove its safety and efficacy.[1] In mid-September, some 42 vaccine candidates were in clinical research: namely 33 in Phase I–II trials and 9 in Phase II–III trials.[1][2][3][4]

Previous work to develop a vaccine against the coronavirus diseases SARS and MERS established considerable knowledge about the structure and function of coronaviruses – which accelerated rapid development during early 2020 of varied technology platforms for a COVID‑19 vaccine.[5]

The World Health Organization (WHO), the Coalition for Epidemic Preparedness Innovations (CEPI), and the Gates Foundation (GF) are committing money and organizational resources for the prospect that several vaccines will be needed to prevent continuing COVID‑19 infection.[6] The CEPI, which is organizing a US$2 billion worldwide fund for rapid investment and development of vaccine candidates,[7] indicated in September that clinical data to support licensure may be available by the end of 2020.[1] On 4 May 2020, the WHO organized a telethon which received US$8.1 billion in pledges from forty countries to support rapid development of vaccines to prevent COVID‑19 infections.[8] At the same time, the WHO also announced the deployment of an international "Solidarity trial" for simultaneous evaluation of several vaccine candidates reaching Phase II–III clinical trials.[9]

Synopsis and history

SARS and MERS

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.[10] 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[11] and MERS[12] 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.[13][14][15] As of 2020, there is no cure or protective vaccine proven to be safe and effective against SARS in humans.[16][17]

There is also no proven vaccine against MERS.[18] 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.[16][19] As of March 2020, there was one (DNA based) MERS vaccine which completed Phase I clinical trials in humans,[20] 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).[21]

COVID-19 vaccine development in 2020

A vaccine for an infectious disease has never before been produced in less than several years, and no vaccine exists for preventing a coronavirus infection in humans.[6] After the coronavirus was detected in December 2019,[22] the genetic sequence of COVID‑19 was published on 11 January 2020, triggering an urgent international response to prepare for the outbreak and hasten development of a preventive vaccine.[23][24][25]

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.[26] 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,[9] with four vaccine candidates entering human evaluation in March (see the table of clinical trials started in 2020, below).[23][27]

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.[9][28] By April 2020, "almost 80 companies and institutes in 19 countries" were working on this virtual gold rush.[29] 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.[1][27][6] Another analysis estimates 10 candidates will need simultaneous initial development, before a select few are chosen for the final path to licensing.[6]

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.[30]

Global development

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.[1]

International organizations

Organizations have formed international alliances to expedite vaccine development and prepare for distribution, including the WHO which is facilitating collaboration, accelerated research, and international communications on a scale unprecedented in history, beginning in early May by raising US$8.1 billion in pledges.[8] The WHO also implemented an Covid-19 Vaccines Global Access (COVAX) for coordinating global vaccine development, the vaccine pillar of Access to COVID-19 Tools (ACT) Accelerator in collaboration with GAVI and the Coalition for Epidemic Preparedness Innovations (CEPI).[1][31][32] 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.[33] COVAX has the goal to accelerate the development and manufacturing of COVID-19 vaccines, and to assure that access to licensed vaccines is equitably provided to all countries.[32]

CEPI is working with international health authorities and vaccine developers to create another US$2 billion fund in a global partnership between public, private, philanthropic, and civil society organizations for accelerated research and clinical testing of eight vaccine candidates, with the 2020–21 goal of supporting several candidates for full development to licensing.[1][27][28] The United Kingdom, Canada, Belgium, Norway, Switzerland, Germany and the Netherlands had already donated US$915 million to CEPI by early May.[8][34] The Bill & Melinda Gates Foundation (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.[35][36]

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 researches 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.[37][38] 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.[39]

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.[40] Major contributions were US$1.6 billion from The Gates Foundation[41] and GB£330 million per year over five years by the UK government (approximately US$2.1 billion in June 2020).[40]

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.[42][43] A further investment of CA$1.1 billion was added to support clinical trials in Canada 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.[44]

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.[34] As of June 2020, six of the eleven COVID‑19 vaccine candidates in early-stage human testing were developed by Chinese organizations.[35] 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.[45] On 18 May, China had pledged US$2 billion to support overall efforts by the WHO for programs against COVID‑19.[46] 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.[47] On August 24, China 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.[48]

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.[49][50] In March, the European Commission made an €80 million investment in CureVac, a German biotechnology company, to develop a mRNA vaccine.[51] The German government announced a separate €300 million investment in CureVac in June.[52] Belgium, Norway, Switzerland, Germany, and the Netherlands have been major contributors to the CEPI effort for COVID‑19 vaccine research in Europe.[34]

In April, the UK 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 UK hospitals, regulations for approval, and eventual manufacturing.[53] The vaccine development initiatives at the University of Oxford and Imperial College of London were financed with GB£44 million in April.[54][55]

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

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.[34][56] 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.[56][57] 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.[58][59] In June, the Warp Speed team said it would work with seven companies developing COVID‑19 vaccine candidates: Moderna, Johnson & Johnson, Merck, Pfizer, and the University of Oxford in collaboration with AstraZeneca, as well as two others.[60]

WHO COVID-19 trials

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.[9] 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;[4] 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[9][61] – 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.[9] 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.[9]

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.[62][63] 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.[61] 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.[61]

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.[61][62]

Partnerships, competition, and distribution

Large pharmaceutical companies with experience in making vaccines at scale, including Johnson & Johnson, AstraZeneca, and GlaxoSmithKline (GSK), are forming alliances with biotechnology companies, national governments, and universities to accelerate progression to an effective vaccine.[34][35] 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.[64]

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).[9] Individual countries producing a vaccine may be persuaded to favor the highest bidder for manufacturing or provide first-service to their own country.[6][24][34] Experts emphasize that licensed vaccines should be available and affordable for people at the frontline of healthcare and having the greatest need.[6][24][34] Under their agreement with AstraZeneca, the University of Oxford vaccine development team and UK government agreed that UK citizens would not get preferential access to a new COVID‑19 vaccine developed by the taxpayer-funded university, but rather consented to having a licensed vaccine distributed multinationally in cooperation with the WHO.[54] 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.[34]

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.[1][9][27][61] 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.[32][65] 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.[23][27][32]

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.[35] As an example, Chinese vaccine developers and the government Chinese Center for Disease Control and Prevention began their efforts in January 2020,[66] 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.[35][67]

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,[34] 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".[34] 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.[6][68] From Phase I clinical trials, 84–90%[23][69]of vaccine candidates fail to make it to final approval during development, and from Phase III, 25.7% fail[69] – the investment by a manufacturer in a vaccine candidate may exceed US$1 billion and end with millions of useless doses.[6][34][35] In the case of COVID‑19 specifically, a vaccine efficacy of 70% may be enough to stop the pandemic, but if it has only 60% efficacy, outbreaks may continue; an efficacy of less than 60% will not provide enough herd immunity to stop the spread of the virus alone.[6]

As the pandemic expands during 2020, research at universities is obstructed by physical distancing and closing of laboratories.[70][71] Globally, supplies critical to vaccine research and development are increasingly scarce due to international competition or national sequestration.[45] 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.[34][35]

Technology platforms

In September, CEPI scientists reported that 9 different technology platforms – with the technology of numerous candidates remaining undefined – were under research and development during 2020 to create an effective vaccine against COVID‑19.[1] According to CEPI, most of the platforms of vaccine candidates in clinical trials as of September are focused on the coronavirus spike protein and its variants as the primary antigen of COVID-19 infection.[1] Platforms being developed in 2020 involve nucleic acid technologies (RNA and DNA), non-replicating viral vectors, peptides, recombinant proteins, live attenuated viruses, and inactivated viruses.[1][5][6][23] 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.[1][5][23] 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.[1][23]

Potential candidates for forming SARS-CoV-2 proteins to prompt an immune response
COVID‑19: Vaccine technology platforms, September 2020[2]
Molecular platform ^ Total number
of candidates
Number of candidates
in human trials
Non-replicating viral vector
31
4 [i]
RNA-based
31
3 [i]
Inactivated virus
14
3 [i]
Protein subunit
76
3 [i]
DNA-based
19
0 [i]
Replicating viral vector
21
0
Virus-like particle
13
0
Live attenuated virus
4
0
  1. ^ a b c d e One or more candidates in Phase II or Phase II–III trials

^ technologies for dozens of candidates are unannounced or "unknown"[2]

Vaccine candidates

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.[1] Some 321 total vaccine candidates are in development as either confirmed projects in clinical trials or in early-stage "exploratory" or "preclinical" development, as of September.[1]

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.[72][73] A Phase I–II trial consists of preliminary safety and immunogenicity testing, is typically randomized, placebo-controlled, while determining more precise, effective doses.[73] 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.[72][73] 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.[74][75][76]

Clinical trials started in 2020

COVID‑19: candidate vaccines in Phase I–III trials[2][3][4]
Vaccine candidates
Developers, sponsors
Technology Current phase (participants)
Design
Completed phase[a] (participants)
Immune response, adverse effects
Locations Duration[b]
AZD1222[c][78][79][80]
University of Oxford, AstraZeneca
Modified chimp adenovirus vector (ChAdOx1) Phase III (30,000)
Interventional; randomized, placebo-controlled study for efficacy, safety, and immunogenicity.[81] Brazil (5,000)[82] International enrollment of the Phase III trial was paused on 8 September 2020 due to an adverse neurological event in one participant,[83][84] but resumed on 12 September after it was determined the symptoms were unrelated to the vaccine.[85]
Phase I-II (543)
Spike-specific antibodies at day 28; neutralizing antibodies after a booster dose at day 56. Adverse effects: pain at the injection site, headache, fever, chills, muscle ache, malaise in more than 60% of participants; paracetamol allowed for some participants to increase tolerability[86]
20 in the UK, São Paulo May 2020 – Aug 2021
Unnamed[87]
Sinopharm: Beijing Institute of Biological Products, Wuhan Institute of Biological Products
Inactivated SARS-CoV-2 (vero cells) Phase III (45,000)
Randomized, double-blind, parallel placebo-controlled, to evaluate safety and protective efficacy in the United Arab Emirates, Bahrain, and Jordan[88]

On September 14, UAE approved Sinopharm's vaccine for emergency use by front-line healthcare workers following successful interim results in the Phase III trials.[89]

Phase I-II (320)
Neutralizing antibodies at day 14 after 2 injections; Adverse effects: injection site pain and fever, which were mild and self-limiting; no serious effects[90]
Jiaozuo, Abu Dhabi Jul 2020 – Jul 2021 in Abu Dhabi
Ad5-nCoV
CanSinoBIO, Beijing Institute of Biotechnology of the Academy of Military Medical Sciences[d]
Recombinant adenovirus type 5 vector Phase III (40,000)
global multi-center, randomized, double-blind, placebo -controlled to evaluate efficacy, safety and immunogenicity[92]
Phase II (508)
Neutralizing antibody and T cell responses. Adverse effects: moderate over 7 days: 74% had fever, pain, fatigue[93]
Wuhan, China

Pakistan

Mar – Dec 2020 in China

Sep 2020 – December 2021 in Pakistan

CoronaVac[94][95][96]
Sinovac, Instituto Butantan
Inactivated SARS-CoV-2 Phase III (10,490)
Double-blind, randomized, placebo-controlled to evaluate efficacy and safety in Brazil (8,870); Indonesia (1,620)
Phase II (600)
Preprint. Immunogenicity eliciting 92% seroconversion at lower dose; Adverse effects: mild in severity, pain at injection site[97]
2 in China; 12 in Brazil; Bandung, Indonesia[98]
  • Jul 2020 – Oct 2021 in Brazil
  • August 2020 – January 2021 in Bandung, Indonesia
BNT162 a1, b1, b2, c2[e][99][100]
BioNTech, Fosun Pharma, Pfizer
mRNA Phase III (30,000)[101]
Randomized, placebo-controlled
Phase I-II (60)
Preprint. Strong RBD-binding IgG and neutralizing antibody response peaked 7 days after a booster dose, robust CD4+ and CD8+ T cell responses, undetermined durability. Adverse effects: dose-dependent and moderate including pain at the injection site, fatigue, headache, chills, muscle and join pain, fever[102][103]
62 in the US, Germany Apr 2020 – May 2021
mRNA-1273[104][105]
Moderna, NIAID, BARDA
Lipid nanoparticle dispersion containing mRNA Phase III (30,000)
Interventional; randomized, placebo-controlled study for efficacy, safety, and immunogenicity
Phase I (45)
Dose-dependent neutralizing antibody response on two-dose schedule; undetermined durability. Adverse effects: fever, fatigue, headache, muscle ache, and pain at the injection site[106][107]
89 in the US Jul 2020 – Oct 2022
Gam-COVID-Vac
Gamaleya Research Institute of Epidemiology and Microbiology; trade name: Sputnik V
Non-replicating viral vector Phase III (40,000)
Randomized double-blind, placebo-controlled to evaluate efficacy, immunogenicity, and safety[108]
Phase I-II (76) Neutralizing antibody and T cell responses. Adverse effects: pain at injection site, fever, headache, weakness, and muscle/joint pain[109] Moscow Aug 2020 – May 2021
Unnamed[2][3][4][110]
Anhui Zhifei Longcom Biopharmaceutical Co. Ltd.
Recombinant protein subunit Phase II (900)
Interventional; randomized, double-blind, placebo-controlled [111]
Phase I (50) Chongqing Jun 2020 – Sep 2021
CVnCoV[112]
CureVac, CEPI
mRNA Phase II (691)
Partially observer-blind, multicenter, controlled, dose-confirmation[113]
Phase I (168) Ghent, 3 in Germany Jun 2020 – Aug 2021
INO-4800[f][114][115]
Inovio, CEPI, Korea National Institute of Health, International Vaccine Institute
DNA plasmid delivered by electroporation Phase I-II (40) Pending Phase I report 3 in the US, Seoul Apr–Nov 2020
Unnamed[116]
Chinese Academy of Medical Sciences
Inactivated SARS-CoV-2 Phase I-II (942)
Randomized, double-blinded, single-center, placebo-controlled
Chengdu Jun 2020 – Sep 2021
AG0301-COVID-19[117]
AnGes Inc.,[118] AMED
DNA plasmid Phase I-II (30)
Non-randomized, single-center, two doses
Osaka Jun 2020 – Jul 2021
Ad26.COV2.S[119]

Janssen Pharmaceutica, BIDMC

Non-replicating viral vector Phase I-II (1,045)
Randomized, double-blinded
8 in US, 5 in Belgium Jul 2020 – 2023
Lunar-COV19/ARCT-021[120][121]

Arcturus Therapeutics

mRNA Phase I-II (92)
Randomized, double-blinded
Singapore Aug 2020 – ?
NVX-CoV2373[122]
Novavax
SARS-CoV-2 recombinant spike protein nanoparticle with adjuvant Phase I (131) Phase I (131)
Preprint. IgG and neutralizing antibody response with adjuvant after booster dose. Adverse effects: short-duration, low grade, local pain, headache, fatigue, myalgia[123][124]
2 in Australia May 2020 – Jul 2021
COVID‑19/aAPC[125]
Shenzhen Genoimmune Medical Institute[126]
Lentiviral vector with minigene modifying aAPCs Phase I (100) Shenzhen Mar 2020 – 2023
LV-SMENP-DC[127]
Shenzhen Genoimmune Medical Institute[126]
Lentiviral vector with minigene modifying DCs Phase I (100) Shenzhen Mar 2020 – 2023
LNP-nCoVsaRNA[128]
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)
4 in the UK Jun 2020 – Jul 2021
GX-19[129][130]
Genexine consortium,[131] International Vaccine Institute
DNA Phase I (40) Seoul Jun 2020 – Jun 2022
SCB-2019[132][133]
Clover Biopharmaceuticals,[134] GSK
Spike protein trimeric subunit with GSK adjuvant Phase I (150) Perth Jun 2020 – Mar 2021
COVAX-19[135]
Vaxine Pty Ltd[136]
Recombinant protein Phase I (40) Adelaide Jun 2020 – Jul 2021
Unnamed[137]
PLA Academy of Military Science, Walvax Biotech[138]
mRNA Phase I (168) 2 in China Jun 2020 – Dec 2021
Unnamed[139][140]
Medicago[141] (governments of Canada and Quebec)
Recombinant plant-based VLP[g] with GSK adjuvant Phase I (180)
Randomized, dose-ranging
2 in Canada Jul 2020 – Apr 2021
SARS-CoV-2 Sclamp[143]
UQ, Syneos Health, CEPI, Seqirus
Molecular clamp stabilized spike protein with MF59 Phase I (120)
Randomised, double-blind, placebo-controlled, dose-ranging
Brisbane Jul–Oct 2020
  1. ^ Latest Phase with published results.
  2. ^ The range from the actual start date of Phase I to the estimated primary completion date of Phase III, when available.
  3. ^ Oxford name: ChAdOx1 nCoV-19. Manufacturing in Brazil to be carried out by Oswaldo Cruz Foundation.[77]
  4. ^ Manufacturing partnership with the National Research Council of Canada and Canadian Center for Vaccinology, Halifax, Nova Scotia[91]
  5. ^ Four vaccines
  6. ^ South Korean Phase I–II in parallel with Phase I in the US
  7. ^ Virus-like particles grown in Nicotiana benthamiana[142]

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.[144] 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.[23]

Industry analysis of past vaccine development shows failure rates of 84–90%.[23][69] 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.[23]

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.[23] 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.[1]

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.[1][23]

Scheduled Phase I trials in 2020

Many vaccine candidates under design or preclinical development for COVID‑19 will not gain approval for human studies in 2020 due to toxicity, ineffectiveness to induce immune responses or dosing failures in laboratory animals, or because of underfunding.[145][146] The probability of success for an infectious disease vaccine candidate to pass preclinical barriers and reach Phase I of human testing is 41-57%.[145]

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.[145][147] 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.[145]

Non-specific vaccines

Some vaccines have non-specific effects beyond the disease they prevent.[148]

Assertions have been made that COVID‑19 mortality has been lower in countries having routine BCG vaccine administered against tuberculosis,[149][150][151][152] though the World Health Organization (WHO) has said there is no evidence that this vaccine is effective against the COVID‑19 virus.[153] In March 2020, a randomized trial of BCG vaccine to reduce COVID‑19 illness began in the Netherlands, seeking to recruit 1,000 healthcare workers.[154] A further randomized trial in Australia is seeking to enroll 4,170 healthcare workers.[155][156]

In June 2020, a randomized placebo-controlled trial to test whether the measles-mumps-rubella vaccine (MMR) can protect healthcare workers from COVID‑19 began with 200 participants in Cairo.[157]

Use of adjuvants

In September 2020, eleven of the vaccine candidates in clinical development used adjuvants to enhance immunogenicity.[1] 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.[158] 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.[158][159] 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.[159] 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.[159] The alum adjuvant initiates diverse molecular and cellular mechanisms to enhance immunogenicity, including release of proinflammatory cytokines.[158][159] A potential drawback of adjuvanted vaccines is that the virus evolves in a way to avoid the induced vaccine response, making the adjuvant-vaccine technology misdesigned against a changed virus.[158] Such a change would require revised manufacturing and increased costs that discourage the routine use of adjuvants.[158][159]

Potential limitations

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.[5][23][160] 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,[69] and CEPI indicates a potential success rate of only 10% for vaccine candidates in 2020 development.[23]

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."[23] However, some 10% of the public perceives vaccines as unsafe or unnecessary, refusing vaccination – a global health threat called vaccine hesitancy[161] – which increases the risk of further viral spread that could lead to COVID‑19 outbreaks.[162] 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.[163][164]

Biosafety concern

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.[5][23]

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 the cytokine storm when the person will be infected by the virus after vaccination.[5][165] 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.[5][165] The antibody response to a vaccine is a variable of vaccine technologies in development, including whether the vaccine has precision in its mechanism,[5] and choice of the route for how it is given (intramuscular, intradermal, oral, or nasal).[165][166]

Efficacy

The effectiveness of new vaccine is defined by its efficacy. The efficacy of less than 60% may result in failure to create herd immunity.[6][166] 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.[166] 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.[166] Further, mutations of the virus can alter its structure targeted by the vaccine, thus making the vaccine ineffective.[167][168]

Enrollment of participants in trials

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.[74] 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.[74] 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.[74] In addition to competition over recruiting participants, clinical trial organizers may encounter people unwilling to be vaccinated due to vaccine hesitancy[162] or disbelieving the science of the vaccine technology and its ability to prevent infection.[169]

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.[74][170]

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.[171] It is not yet known if it is possible to create a safe, reliable and affordable vaccine for this virus, and it is not yet known exactly how much the vaccine development will cost.[6][24][35] It is possible that billions of dollars could be invested without success.[34]

The European Commission organized and held a video conference of world leaders on 4 May 2020, at which US$8 billion was raised for COVID-19 vaccine development.[172]

After a vaccine is created, billions of doses will 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.[173]

Proposed challenge studies

Strategies are being considered for fast-tracking the licensing of a vaccine against COVID‑19, especially by compressing (to a few months) the usually lengthy duration of Phase II–III trials (typically many years).[174][175][176] Challenge studies have been implemented previously for diseases less deadly than COVID‑19 infection, such as common influenza, typhoid fever, cholera, and malaria.[175][177] Following preliminary proof of safety and efficacy of a candidate vaccine in laboratory animals and healthy humans, controlled challenge studies might be implemented to bypass typical Phase III research, providing an accelerated path to license a COVID‑19 vaccine.[174][177][175]

A challenge study begins by simultaneously testing a vaccine candidate for immunogenicity and safety in laboratory animals and healthy adult volunteers (100 or fewer), something normally a sequential process using animals first.[174][175] If the initial tests are promising, the study proceeds by rapidly advancing the effective dose into a large-scale Phase II–III trial in previously-uninfected, low-risk volunteers (such as young adults), who would then be deliberately infected with COVID‑19 for comparison with a placebo control group.[174][175][177] Following the challenge, the volunteers would be monitored closely in clinics with life-saving resources, if needed.[174][175] Volunteering for a vaccine challenge study during the COVID‑19 pandemic is likened to the emergency service of healthcare personnel for COVID‑19-infected people, firefighters, or organ donors.[174]

Although challenge studies are ethically questionable due to the unknown hazards for the volunteers of possible COVID‑19 disease enhancement and whether the vaccine received has long-term safety (among other cautions), challenge studies may be the only option to rapidly produce an effective vaccine that will minimize the projected millions of deaths worldwide from COVID‑19 infection,[174][178] according to some infectious disease experts.[174][175][177] 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.[179]

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.[180] 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.[180] 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 US Food and Drug Administration (FDA).[181][182]

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.[180] 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.[183] 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.[183]

World Health Organization

Vaccines developed for multinational distribution via the United Nations Children's Fund (UNICEF) require pre-qualification by WHO to ensure international standards of quality, safety, immunogenicity, and efficacy for adoption by numerous countries.[180]

The process requires manufacturing consistency at WHO-contracted laboratories following GMP practices.[180] 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. WHO works with national agencies to monitor inspections of manufacturing facilities and distributors for compliance with GMP and regulatory oversight.[180]

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.[180]

Europe

In the European Union (EU), vaccines for pandemic pathogens, such as seasonal influenza, are licensed either continent-wide where all Member States comply ("centralized"), for only some Member States ("decentralized"), or on an individual national level.[181] Generally, all EU countries follow regulatory guidance and clinical programs defined by the European Committee for Medicinal Products for Human Use (CHMP), a scientific panel of the EMA responsible for vaccine licensure.[181] CHMP is supported by several expert groups who assess and monitor the progress of a vaccine before and after licensure and distribution.[181]

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.[184] 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.[184]

As of August 2020 in the United States, there is no national strategy for how a successful vaccine will be ethically prioritized or distributed to vulnerable population segments, such as homeless and incarcerated people and the elderly.[163][183][185] 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.[184]

Emergency use authorization

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.[186] 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.[186]

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 CHMP to evaluate clinical data in real time, enabling a promising vaccine candidate to be approved on a rapid timeline by the EMA.[187]

In the United States, the FDA may grant Emergency Use Authorization for a promising COVID-19 vaccine before full evidence is available about its safety and efficacy, but this hastened process has been criticized for its political misuse, potential for lowered standards, and increased antivaccine sentiment in the US population during 2020.[163][188][189]

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.[180][184] The WHO works with UN member states to implement postlicensing surveillance.[180] The FDA relies on a Vaccine Adverse Event Reporting System to monitor safety concerns about a vaccine throughout its use in the American public.[184]

Commercialization and equitable access

Commercialization issues

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.[24][190][191][192] 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.[24][35][191] 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 UK government and university as public partners had commercialization rights.[192] AstraZeneca stated that initial pricing of its vaccine would not include a profit margin for the company while the pandemic was still expanding.[192]

In early June, AstraZeneca made a USD$750 millon 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.[193] 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.[24][34][35][190] 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.[194] 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.[194]

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,[191][195] 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.[192][196][197] 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.[195]

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;[193] SII indicated that India will get the doses as required by the Indian government.[198] Similar preferential homeland distribution may exist if a vaccine is manufactured in Australia.[199] Amid concerns that vaccines produced in China would be distributed there first, the Chinese government pledged in May that a successful Chinese vaccine would become a "global, public good," inferring enough doses would be manufactured for both national and global distribution.[200]

Equitable access

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.[7][8][40][190] 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.[27]

Having been created to monitor fair distribution of infectious disease vaccines to low- and middle-income countries,[195][201] 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.[201] Some vaccine manufacturers opposed parts of these proposals.[191][201]

International groups, such as the Centre for Artistic Activism and Universities Allied for Essential Medicines, advocate for equitable access to licensed COVID‑19 vaccines.[202][203] 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,[195][201] particularly urgent vaccinations provided first for healthcare workers, vulnerable populations, and children.[24][190][191] During 2020, the WHO, GAVI, and CEPI combined resources to form COVAX – a program for coordination of global equitable access to a licensed vaccine.[32][33]

Over 100 international scientists and concerned individuals (including those associated with religious organizations) have called for releasing COVID‑19 vaccines to the public domain. 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.[204]

Supply chain

During and after 2021, 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.[6][205][206] 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.[205][207][208] 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."[209]

As an example highlighting the immensity of the challenge, the International Air Transport Association stated that 8,000 747 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.[210] GAVI states that "with a fast-moving pandemic, no one is safe, unless everyone is safe."[32]

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.[205][207][211] 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.[32][212] In September, the COVAX partnership included 172 countries coordinating plans to optimize the supply chain for a COVID-19 vaccine,[213] 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.[214][215]

Logistics

Logistics vaccination services assure necessary equipment, staff, and supply of licensed vaccines across international borders.[216] Central logistics include vaccine handling and monitoring, cold chain management, and safety of distribution within the vaccination network.[217] 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.[32][211] Included are logistics tools for vaccine forecasting and needs estimation, in-country vaccine management, potential for wastage, and stock management.[217]

Other logistics factors conducted internationally during distribution of a COVID-19 vaccine may include:[205][218][219]

  • 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.[220] If the vaccine supply chain fails, the economic and human costs of the pandemic may be extended for years.[208]

Manufacturing capacity

By August 2020 when only a few vaccine candidates were in Phase III trials many months from establishing safety and efficacy, numerous governments pre-ordered more than two billion doses at a cost of more than US$5 billion.[206][220][221] Pre-orders from the UK government for 2021 were for five vaccine doses per person, a number dispiriting organizations like the WHO and GAVI which are promoting fair and equitable access worldwide, especially for developing countries.[206] 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.[213] Overall 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.[6][220][206] As middle-income countries, Brazil and Indonesia have pre-ordered millions of vaccine doses, and the Serum Institute of India, a major vaccine manufacturer, plans to produce at least one billion vaccine doses, although the Institute has stated that half the doses will be used in India.[206]

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."[222] Preparing for high demand in manufacturing vials, an American glass producer invested $163 million in July for a vial factory.[223] Glass availability for vial manufacturing and contaminant control are issues of concern,[224] indicating higher production costs with lower profit potential for developers amid demands for vaccines to be affordable.[32][206][208]

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.[206][220] The scale of the COVID-19 vaccine supply chain is expected to be vast to ensure delivery worldwide to vulnerable populations.[6][207] Priorities for preparing facilities for such distribution include temperature-controlled facilities and equipment, optimizing infrastructure, training immunization staff, and rigorous monitoring.[207][209][214] RFID technologies are being implemented to track and authenticate a vaccine dose from the manufacturer along the entire supply chain to the vaccination.[225]

Cold chain

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).[219][226] 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.[226] Freezing damage and inadequate training of personnel in the local vaccination process are major concerns.[227] 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.[226]

DNA and RNA vaccine technologies are in development, but may be difficult to manufacture at scale and control degradation during cold storage and transport.[208] As examples, Moderna's RNA vaccine candidate requires cold chain management just above freezing temperatures with limited storage duration, but the BioNTech-Pfizer RNA candidate requires storage at -70°C (-94°F) or colder throughout deployment until vaccination.[6][228]

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.[228] 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.[205][228] 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.[6][214][229]

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.[207][210][230] "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.[230]

For the severe reduction in passenger air traffic during 2020, airlines downsized personnel, trimmed destination networks, and put aircraft into long-term storage.[207][230] 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.[214][230]

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.[211][231] Anticorruption, transparency, and accountability safeguards are being established to reduce and eliminate corruption of COVID-19 vaccine supplies.[231][232] 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.[231] Tracking system technologies for packaging are being used by manufacturers to trace vaccine vials across the supply chain,[211] and to use digital and biometric tools to assure security for vaccination teams.[225][233]

National infrastructure

The WHO has implemented an "Effective Vaccine Management" system,[234] 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:[216][234]

  • 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 February 4, 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".[235] The declaration is effective in the United States through October 1, 2024.

Misinformation

Social media posts have promoted a conspiracy theory that a COVID‑19 vaccine is already available. The patents cited by various social media posts have references to existing patents for genetic sequences and vaccines for other strains such as the SARS coronavirus, but not for COVID‑19.[236][237]

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".[238]

See also

References

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