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. 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. early development niaid (nih) scientist researching covid‑19 vaccine examines agar plate. (30 january 2020) after a coronavirus was isolated in december 2019, 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. 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. the rapidly growing infection rate of covid‑19 worldwide during 2020 stimulated international alliances and government efforts to urgently organize resources to make multiple vaccines on shortened timelines, with four vaccine candidates entering human evaluation in march (see the table of clinical trials started in 2020, below). by april 2020, "almost 80 companies and institutes in 19 countries" were working on this virtual gold rush. 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. another analysis estimates ten candidates will need simultaneous initial development, before a select few are chosen for the final path to licensing. cyber-espionage efforts in july 2020, the uk's national cyber security centre, the canadian communications security establishment, and the u.s.'s homeland security department cybersecurity and infrastructure security agency, and the national security agency (nsa) issued a joint statement saying that russian state-backed hackers, specifically cozy bear (apt29) were attempting to steal covid‑19 treatment and vaccine research from academic and pharmaceutical institutions in other countries. russia denied the claim, but has a history of cyber-espionage and cyberattacks on foreign targets. in november 2020, microsoft reported that the russian state-sponsored hacking group fancy bear (apt28) and north korean state-sponsored hacking groups nicknamed "zinc" and "cerium" had been implicated in recent cyberattacks against researchers developing a covid-19 vaccine (including in canada, france, india, south korea, and the u.s.) as well as against the world health organization, and that the cyberattackers had used both brute force and phishing techniques to compromise computer systems. microsoft reported that at least nine healthcare institutions were targeted, and that some attempts were successful. in february 2021, south korean's national intelligence service gave a closed-door briefing to members of the south korean parliament about north korean efforts to steal covid-19 vaccine technology from pfizer. preclinical research niaid (nih) scientist researching covid‑19 vaccine. (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. 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. industry analysis of past vaccine development shows failure rates of 84–90%. 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. to assess the potential for vaccine efficacy, unprecedented computer simulations and new covid‑19-specific animal models are being developed multinationally. 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. 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%. 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. 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, and cepi indicates a potential success rate of only 10% for vaccine candidates in 2020 development. research at universities is obstructed by physical distancing and closing of laboratories. 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. antibody-dependent enhancement main article: antibody-dependent enhancement although the quality and quantity of antibody production by a potential vaccine is intended to neutralize the covid‑19 infection, a vaccine may have an unintended opposite effect by causing antibody-dependent disease enhancement (ade), which increases the virus attachment to its target cells and might trigger a cytokine storm if a vaccinated person is later attacked by the virus. 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. the antibody response to a vaccine is a variable of vaccine technologies in development, including whether the vaccine has precision in its mechanism, and choice of the route for how it is given (intramuscular, intradermal, oral, or nasal). prior to the pandemic, ade was observed in animal studies of laboratory rodents with vaccines for sars-cov, the virus that causes severe acute respiratory syndrome (sars). researchers therefore emphasized the need to carefully assess the potential for ade to occur with covid-19. however, as of 27 january 2022 there have been no observed incidences with vaccines for covid-19 in trials with nonhuman primates, in clinical trials with humans, or following the widespread use of approved vaccines. 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. 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; 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 – 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. 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. 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. a phase i–ii trial consists of preliminary safety and immunogenicity testing, is typically randomized, placebo-controlled, while determining more precise, effective doses. 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. 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. phase iii trials of astrazeneca's intervention started 28 august 2020 and ended 5 march 2021. in january 2022 'moderna' and 'pfizer' both started trials of vaccine tailored to immunize against the omicron variant. see response by vaccine producers for vaccine development aimed at providing immunity to omicron. 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. 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. 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. in addition to competition over recruiting participants, clinical trial organizers may encounter people unwilling to be vaccinated due to vaccine hesitancy or disbelieving the science of the vaccine technology and its ability to prevent infection. 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. eligibility criteria for astrazeneca's phase iii trial included: ages, 18 to 130 years, all sexes, and healthy volunteers. inclusion criteria specified, increased risk of sars-cov-2 infection and medically stable. exclusion criteria included; 1) confirmed or suspected immunosuppressive or immunodeficient state, 2) significant disease, disorder, or finding, and 3) prior or concomitant vaccine therapy for covid‑19. 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. 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. 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. 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. 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. 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. challenge studies have been used for diseases less deadly than covid‑19 infection, such as common influenza, typhoid fever, cholera, and malaria. the world health organization 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. 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. 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. authorizations and licensure at the beginning