COVID-19 vaccine clinical research uses clinical research to establish the characteristics of COVID-19 vaccines. These characteristics include efficacy, effectiveness, and safety. , 40 vaccines are authorized by at least one national regulatory authority for public use: one DNA vaccine: ZyCoV-D four RNA vaccines: Pfizer–BioNTech, Moderna, Walvax, and Gemcovac twelve inactivated vaccines: Chinese Academy of Medical Sciences, CoronaVac, Covaxin, CoviVac, COVIran Barekat, FAKHRAVAC, Minhai-Kangtai, QazVac, Sinopharm BIBP, WIBP, Turkovac, and VLA2001. six viral vector vaccines: Sputnik Light, Sputnik V, Oxford–AstraZeneca, Convidecia, Janssen, and iNCOVACC sixteen subunit vaccines: Abdala, Corbevax, COVAX-19, EpiVacCorona, IndoVac, MVC-COV1901, Noora, Novavax, Razi Cov Pars, Sanofi–GSK, Sinopharm CNBG, Skycovione, Soberana 02, Soberana Plus, V-01, and ZF2001. one virus-like particle vaccine: CoVLP
Formulation A wide variety of technologies are being used to formulate vaccines against COVID-19. The development and deployment of mRNA vaccines and viral vector vaccines has been outstandingly rapid and can be described as revolutionary. However, global vaccine equity against COVID-19 has not been achieved. Conventional vaccine manufacturing approaches using whole inactivated virus (WIV), protein-based subunit vaccines, and virus-like particles (VLPs) may offer advantages in the development of vaccines for use in low- and middle-income countries (LMICs) and in addressing vaccine access gaps.
Many vaccine candidates use adjuvants to enhance immunogenicity, as part of the delivery system or as an accompanying immune stimulant. Vaccine adjuvant formulations using aluminum salts or "alum" may be particularly effective for technologies using inactivated COVID-19 virus and for recombinant protein-based or vector-based vaccines.
Status
Clinical trials
The clinical trial process typically consists of three phases, each following the success of the prior phase. Trials are doubly blind in that neither the researcher nor the subject know whether they receive the vaccine or a placebo. Each phase involves randomly-selected subjects who are randomly assigned to serve either as recipients are controls: Phase I trials test primarily for safety and preliminary dosing in healthy subjects. Dozens of subjects. Phase II trials evaluate immunogenicity, dose levels (efficacy based on biomarkers) and adverse effects. Hundreds of subjects. Sometimes Phase I and II trials are combined. 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 selected dose. Safety, efficacy, and clinical endpoints may vary, including the definition of side effects, infection or amount of transmission, and whether the vaccine prevents moderate or severe infection.
A clinical trial design in progress may adopt an "adaptive design". If accumulating data provide insights about the treatment, the endpoints or other aspects or the trial can be adjusted. Adaptive designs may shorten trial durations and use fewer subjects, possibly expediting decisions, avoiding duplication of research efforts, and enhancing coordination of design changes.
Vaccine candidates in human trials The table below shows various vaccine candidates and the phases which they had completed per the references. Current phases are also shown along with other details. COVID-19 candidate vaccines in Phase I–III trials
Homologous prime-boost vaccination
In July 2021, the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) issued a joint statement reporting that a booster dose is not necessary for those who have been fully vaccinated.
In August 2021, the FDA and the CDC authorized the use of an additional mRNA vaccine dose for immunocompromised individuals. The authorization was extended to cover other specific groups in September 2021.
In October 2021, the FDA and the CDC authorized the use of either homologous or heterologous vaccine booster doses.
Heterologous prime-boost vaccination
The World Health Organization (WHO) defines heterologous prime-boost immunization as the "administration of two different vectors or delivery systems expressing the same or overlapping antigenic inserts." A heterologous scheme can sometimes be more immunogenic than some homologous schemes.
In October 2021, the FDA and the CDC authorized the use of either homologous or heterologous vaccine booster doses.
Some experts believe that heterologous prime-boost vaccination courses can boost immunity, and several studies have begun to examine this effect. Despite the absence of clinical data on the efficacy and safety of such heterologous combinations, Canada and several European countries have recommended a heterologous second dose for people who have received the first dose of the Oxford–AstraZeneca vaccine.
In February 2021, the Oxford Vaccine Group launched the Com-COV vaccine trial to investigate heterologous prime-boost courses of different COVID-19 vaccines. As of June 2021, the group is conducting two phase II studies: Com-COV and Com-COV2.
In Com-COV, the two heterologous combinations of the Oxford–AstraZeneca and Pfizer–BioNTech vaccines were compared with the two homologous combinations of the same vaccines, with an interval of 28 or 84 days between doses.
In Com-COV2, the first dose is the Oxford–AstraZeneca vaccine or the Pfizer vaccine, and the second dose is the Moderna vaccine, the Novavax vaccine, or a homologous vaccine equal to the first dose, with an interval of 56 or 84 days between doses.
A study in the UK is evaluating annual heterologous boosters by randomly combining the following vaccines: Oxford–AstraZeneca, Pfizer–BioNTech, Moderna, Novavax, VLA2001, CureVac, and Janssen.
On 16 December, WHO recommendations on heterologous vaccinations suggested a general trend of increased immunogenicity when one of the doses is of an mRNA vaccine, particularly as the last dose. The immunogenicity of a homologous mRNA course is roughly equivalent to a heterologous scheme involving a vector vaccine and an mRNA vaccine. However, the WHO has emphasized the need to address many evidence gaps in heterologous regimens, including duration of protection, optimal interval between doses, influence of fractional dosing, effectiveness against variants and long-term safety.
+Heterologous second dose regimes in clinical trialFirst doseSecond doseSchedulesCurrent phase (participants), periods and locationsSputnik LightDays 0 and 5684ConvideciaZF2001Oxford–AstraZenecaPfizer–BioNTechDays 0 and 28Days 0 and 42Oxford–AstraZenecaPfizer–BioNTechJanssenDays 0 and 84
+Heterologous booster dose regimes in clinical trialInitial courseBooster doseIntervalCurrent phase (participants), periods and locationsCoronaVac (2 doses)19 weeks or more
Efficacy
Vaccine efficacy is the reduction in risk of getting the disease by vaccinated participants in a controlled trial compared with the risk of getting the disease by unvaccinated participants. An efficacy of 0% means that the vaccine does not work (identical to a placebo). An efficacy of 50% means that there are half as many cases of infection as in unvaccinated individuals.
COVID-19 vaccine efficacy may be adversely affected if the arm is held improperly or squeezed so the vaccine is injected subcutaneously instead of into the muscle. The CDC guidance is to not repeat doses that are administered subcutaneously.
It is not straightforward to compare the efficacies of the different vaccines because the trials were run with different populations, geographies, and variants of the virus. In the case of COVID-19 prior to the advent of the delta variant, it was thought that a vaccine efficacy of 67% may be enough to slow the pandemic, but the current vaccines do not confer 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. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) set a cutoff of 50% as the efficacy required to approve a COVID-19 vaccine, with the lower limit of the 95% confidence interval being greater than 30%. Aiming for a realistic population vaccination coverage rate of 75%, and depending on the actual basic reproduction number, the necessary effectiveness of a COVID-19 vaccine is expected to need to be at least 70% to prevent an epidemic and at least 80% to extinguish it without further measures, such as social distancing.
The observed substantial efficacy of certain mRNA vaccines even after partial (1-dose) immunization indicates a non-linear dose-efficacy relation already seen in the phase I-II study. It suggests that personalization of the vaccine dose (regular dose to the elderly, reduced dose to the healthy young, additional booster dose to the immunosuppressed) might allow accelerating vaccination campaigns in settings of limited supplies, thereby shortening the pandemic, as predicted by pandemic modeling.
Ranges below are 95% confidence intervals unless indicated otherwise, and all values are for all participants regardless of age, according to the references for each of the trials. By definition, the accuracy of the estimates without an associated confidence interval is unknown publicly. Efficacy against severe COVID-19 is the most important, since hospitalizations and deaths are a public health burden whose prevention is a priority. Authorized and approved vaccines have shown the following efficacies:
COVID-19 vaccine efficacy
Effectiveness
Evidence from vaccine use during the pandemic shows vaccination can reduce infection and is most effective at preventing severe COVID-19 symptoms and death, but is less good at preventing mild COVID-19. Efficacy wanes over time but can be maintained with boosters. In 2021, the CDC reported that unvaccinated people were 10 times more likely to be hospitalized and 11 times more likely to die than fully vaccinated people.
The CDC reported that vaccine effectiveness fell from 91% against Alpha to 66% against Delta. One expert stated that "those who are infected following vaccination are still not getting sick and not dying like was happening before vaccination." By late August 2021, the Delta variant accounted for 99 percent of U.S. cases and was found to double the risk of severe illness and hospitalization for those not yet vaccinated.
On 10 December 2021, the UK Health Security Agency reported that early data indicated a 20- to 40-fold reduction in neutralizing activity for Omicron by sera from Pfizer 2-dose vaccinees relative to earlier strains. After a booster dose (usually with an mRNA vaccine), vaccine effectiveness against symptomatic disease was at , and the effectiveness against severe disease was expected to be higher.
A meta-analysis looking into COVID-19 vaccine differences in immunosuppressed individuals found that people with a weakened immune system are less able to produce neutralizing antibodies. For example, organ transplant recipients need three vaccines to achieve seroconversion. A study on the serologic response to mRNA vaccines among patients with lymphoma, leukemia, and myeloma found that one-quarter of patients did not produce measurable antibodies, varying by cancer type.
In February 2023, a systematic review in The Lancet said that the protection afforded by infection was comparable to that from vaccination, albeit with an increased risk of severe illness and death from the disease of an initial infection.