Coronavirus disease 2019 (COVID-19): Vaccines to prevent SARS-CoV-2 infection

Authors:Kathryn M Edwards, MDWalter A Orenstein, MDSection Editor:Martin S Hirsch, MDDeputy Editor:Allyson Bloom, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Nov 2020. | This topic last updated: Dec 02, 2020.

What’s New

Vaccines to prevent SARS-CoV-2 infection (November 2020)

Vaccines to prevent SARS-CoV-2 infection are considered the most promising approach for controlling the pandemic. Several vaccine candidates have demonstrated immunogenicity without major safety concerns in early-phase human trials. Two mRNA vaccine candidates (BNT162b2 and mRNA-1273) have been reported in press-released results of large placebo-controlled trials to have 95 percent efficacy in preventing laboratory-confirmed symptomatic COVID-19 [1,2]. They also prevented severe COVID-19. An adenovirus vector vaccine (AZD1222) was reported to have 70 percent efficacy [3]. Full trial reports are needed to critically assess the vaccines’ impact and safety, including the effect on asymptomatic SARS-CoV-2 infection, which could have implications for transmission. (See “Coronavirus disease 2019 (COVID-19): Vaccines to prevent SARS-CoV-2 infection”.)

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INTRODUCTION

At the end of 2019, a novel coronavirus now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the cause of a cluster of pneumonia cases in Wuhan, a city in the Hubei Province of China. It rapidly spread, resulting in a global pandemic. In February 2020, the World Health Organization named the disease COVID-19, which stands for coronavirus disease 2019 [1].

Vaccines to prevent SARS-CoV-2 infection are considered the most promising approach for curbing the pandemic and are being vigorously pursued. As of fall 2020, over 40 candidate vaccines were in human trials and over 150 were in preclinical trials. The World Health Organization maintains an updated list of vaccine candidates under evaluation [2].

This topic will cover vaccines for SARS-CoV-2, with a focus on vaccines in the later stages of development, as well as anticipated issues related to licensure, allocation, uptake, and post-licensure monitoring. Other aspects related to prevention of COVID-19 are discussed in detail elsewhere. (See “Coronavirus disease 2019 (COVID-19): Epidemiology, virology, and prevention”, section on ‘Prevention’.)

GENERAL PRINCIPLES

Overview of vaccine development — As with the development of pharmaceuticals, vaccine development progresses through preclinical evaluation and three distinct clinical stages, phases I, II, and III [3]. Traditionally, these steps occur sequentially, and each usually takes several years for completion. SARS-CoV-2 vaccine development has accelerated to an unprecedented pace, with each step occurring over several months. Nevertheless, safety criteria remain stringent. In the United States, the Food and Drug Administration (FDA) must approve progression to each next step in human trials, from initiation of phase I trials through progression to phase III trials, based on data generated in the prior step:

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Preclinical studies – Initially, early vaccine candidates are administered to small animals, often mice, and the resulting immune responses are measured. The vaccine must generate an immune response to undergo further testing. Toxicity studies are also conducted in animals to detect any safety concerns.

With SARS-CoV-2, nonhuman primate models of infection have been employed; in these preclinical studies, primates are vaccinated then challenged with wild-type SARS-CoV-2 [4,5]. Because of concerns that vaccines might enhance subsequent disease, which had been observed in animal studies with other coronavirus vaccines, specific immunologic criteria have been proposed for preclinical SARS-CoV-2 vaccine studies [6]; studies to date have not identified evidence of SARS-CoV-2 vaccine-associated enhanced disease. (See ‘Lessons from SARS-CoV-1 and MERS-CoV vaccines’ below.)

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Phase I clinical trials – Vaccines that stimulate an immune response without toxicity concerns in animal studies progress to phase I human trials. These trials enroll healthy subjects, usually fewer than 100 individuals, generally between the ages of 18 to 55 years. The primary objective is to test the safety of the experimental vaccine, although immunogenicity is also measured. Phase I studies also often involve dose-ranging studies, so that the first enrolled subjects are administered the lowest doses of vaccine and, if tolerated, the doses are increased in subsequent subjects.

Subjects enrolled in phase I studies are screened for their ability to be closely monitored and comply with rigorous safety assessments. These assessments include daily monitoring of local and systemic adverse events with measurement of temperature, as well as swelling and size of redness at the injection site. There are also detailed assessments of systemic reactions that result in limitations of normal activities. Most of these phase I studies have data safety and monitoring committees (DSMCs) composed of independent vaccine experts and study sponsors; they assess adverse events that follow vaccination and approve dose advancement. All phase I studies also have halting rules, so that if severe reactions are seen, the study is stopped.

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Phase II clinical trials – These trials are planned to expand the safety profile and immune response assessment in larger numbers of subjects, generally several hundred. As with phase I trials, there is meticulous attention to safety assessment and input by an independent DSMC to assess the reaction profile. In the COVID-19 vaccine initiative, phase I and II and phase II and III studies have frequently been combined with a seamless transition from one phase into the next.

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Phase III clinical trials – These trials are designed to determine whether the vaccines prevent a predefined endpoint related to infection, usually laboratory-confirmed disease. Subjects enrolled in phase III studies are randomly assigned and blinded to receipt of either vaccine or a control preparation, typically a placebo, although some studies use a comparator vaccine. When study participants develop symptoms or signs of disease, they are tested for the pathogen. Vaccine efficacy in percent is the reduction in specific disease incidence among those who received vaccine versus those who received the control product and is assessed by the following formula: ((attack rate in the unvaccinated – attack rate in the vaccinated)/attack rate in the unvaccinated) x 100. Efficacy criteria for SARS-CoV-2 trials are discussed elsewhere. (See ‘Establishing efficacy’ below.)

Lessons from SARS-CoV-1 and MERS-CoV vaccines — Vaccine development for SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) paved the way for rapid development of SARS-CoV-2 vaccines. Pre-clinical studies were completed with SARS-CoV-1 vaccines, and two vaccines were evaluated in small human trials; however, further work was halted once the virus was eliminated from circulation [7,8]. After MERS-CoV emerged, preclinical vaccine studies and phase I human studies were conducted against this agent [9,10].

Antigenic target — The major antigenic target for both SARS-CoV-1 and MERS vaccines was the large surface spike protein [11-13]. An analogous protein is also present in SARS-CoV-2 (figure 1); it binds to the angiotensin-converting enzyme 2 (ACE2) receptor on host cells and induces membrane fusion (figure 2) [14]. Based on data from SARS-CoV-1 and MERS-CoV vaccine studies, as well as observations that antibodies binding to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein can prevent attachment to the host cell and neutralize the virus, the spike protein became the predominant antigenic target for SARS-CoV-2 vaccine development [15].

Vaccine-enhanced disease — Animal studies of vaccines for SARS-CoV-1 and MERS-CoV had raised concerns for enhanced disease with vaccination; after challenge with wild-type virus, some previously vaccinated animals developed non-neutralizing antibody and Th2 cell responses that were associated with eosinophilic lung inflammation [16-18]. No enhanced disease was seen in any human studies. Nevertheless, specific immunologic parameters had been proposed for animal and human studies to reduce the risk of enhanced disease with SARS-CoV-2 vaccines [6]. These include criteria for neutralizing antibody and Th1-polarized cellular immune responses.

Immunologic basis for SARS-CoV-2 vaccination — Several observations support the concept that vaccination has the potential to prevent SARS-CoV-2 infection. In nonhuman primate studies, experimental infection with wild-type SARS-CoV-2 virus protected against subsequent reinfection, indicating that infection can result in protective immunity [19,20]. Vaccination of primates also protected against viral challenge; development of functional neutralizing antibodies correlated with protection [21-23]. Epidemiologic studies in humans have also suggested that neutralizing antibodies are associated with protection from infection, as illustrated in an outbreak on a fishing vessel [24]. Thus, vaccines that elicit a sufficient neutralizing response should be able to offer protection against COVID-19. (See “Coronavirus disease 2019 (COVID-19): Epidemiology, virology, and prevention”, section on ‘Immunity following infection’.)

The site of vaccine delivery may impact the character of the immune response [15]. Natural respiratory infections elicit both mucosal and systemic immune responses. Most vaccines, however, are administered intramuscularly (or intradermally) and elicit primarily a systemic immune response, with less robust protection in the upper respiratory mucosa than after natural infection. Some vaccines can be administered intranasally, approximating natural infection, and these may elicit a mucosal immune response, although they typically do not induce as high of a systemic antibody response as inactivated vaccines do [25,26]. Live attenuated COVID-19 vaccines administered to the respiratory tract are undergoing preclinical studies. (See ‘Vaccine platforms’ below.)

Vaccine platforms — SARS-CoV-2 vaccines are being developed using several different platforms (figure 3) [15]. Some of these are traditional approaches, such as inactivated virus or live attenuated viruses, which have been used for inactivated influenza vaccines and measles vaccine, respectively. Other approaches employ newer platforms, such as recombinant proteins (used for human papillomavirus vaccines) and vectors (used for Ebola vaccines). Some platforms, such as RNA and DNA vaccines, have never been employed in a licensed vaccine. General descriptions of the different platforms used for SARS-CoV-2 vaccines are presented here. Examples of specific SARS-CoV-2 vaccines developed using these different platforms are discussed in detail elsewhere. (See ‘Vaccine candidates in late-phase studies’ below.)

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Inactivated vaccines – Inactivated vaccines are produced by growing SARS-CoV-2 in cell culture then chemically inactivating the virus [27,28]. The inactivated virus is often combined with alum or another adjuvant in the vaccine to stimulate an immune response. Inactivated vaccines are typically administered intramuscularly. They require a biosafety level 3 facility for production. Immune responses to a SARS-CoV-2 inactivated vaccine would target not only the spike protein but also other components of the virus. Prototype inactivated SARS-CoV-2 vaccines are being developed in China, India, and Kazakhstan; several are in late-stage clinical trials. (See ‘Vaccine candidates in late-phase studies’ below.)

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Live attenuated vaccines – Live attenuated vaccines are produced by developing genetically weakened versions of the wild-type virus; these weakened viruses replicate in the recipient to generate an immune response but do not cause disease [27,28]. Attenuation can be achieved by modifying the virus genetically or by growing it in adverse conditions so that virulence is lost but immunogenicity is maintained. A live attenuated SARS-CoV-2 vaccine would hopefully stimulate both humoral and cellular immunity to multiple components of the whole attenuated virus. Another advantage of live vaccines is that they can be administered intranasally, as with the live attenuated influenza vaccine, which might induce mucosal immune responses at the site of viral entry in the upper respiratory tract. However, safety concerns with live attenuated vaccines include reversion to or recombination with the wild-type virus. Several live attenuated SARS-CoV-2 vaccines are in pre-clinical development, but none have reached human trials [2].

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Recombinant protein vaccines – Recombinant protein vaccines are composed of viral proteins that have been expressed in one of various systems, including insect and mammalian cells, yeast cells, and plants. These vaccines are typically administered intramuscularly. They do not require replication of the live virus, which facilitates production, although production yields depend on the ability to express the spike protein, which is variable. Recombinant SARS-CoV-2 vaccines in development include recombinant spike protein vaccines, recombinant RBD vaccines, and virus-like particle (VLP) vaccines [2]. A recombinant spike protein vaccine in late-phase clinical trials is discussed elsewhere. (See ‘Vaccine candidates in late-phase studies’ below.)

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Vector vaccines

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Replication-incompetent vector vaccines – Replication-incompetent vector vaccines use a different vector virus that has been engineered to not replicate in vivo and to express the viral protein that is the intended immune target. Many replication-incompetent vector vaccine candidates use adenovirus vectors, but other vectors include modified vaccinia Ankara (MVA), human parainfluenza virus, influenza virus, adeno-associated virus (AAV), and Sendai virus [2]. One drawback to vector vaccines is that pre-existing immunity to the vector can attenuate immunogenicity of the vaccine [29]. This can be avoided by using viral vectors that are uncommon in humans, vectors derived from animal viruses, such as a chimpanzee adenovirus, or vectors that do not induce self-immunity, such as AAV. Most SARS-CoV-2 replication-incompetent vector vaccines in development are administered intramuscularly and are engineered to express the spike protein, with a resultant host immune response to that protein. Several are in late phase clinical trials. (See ‘Vaccine candidates in late-phase studies’ below.)

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Replication-competent vector vaccines – Replication-competent vectors are derived from attenuated or vaccine strains of viruses. Using replication-competent vectors often results in a more robust immune response than with replication-incompetent vectors, since they replicate within the vaccinated individual and trigger an innate immune response. Among SARS-CoV-2 vaccine candidates, replication-competent vectors have been engineered to express the spike protein in measles vaccine strain vectors, influenza virus-based vectors, vesicular stomatitis virus (VSV) [2], and Newcastle disease virus (NDV) [2,30,31]. NDV-based vectors propagate to high titers in eggs and could be produced using the global influenza vaccine production pipeline; they could also be given intranasally to stimulate mucosal immunity at the site of viral entry. Several replication-competent vector vaccines are in early-phase clinical trials.

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Inactivated virus vector vaccines – Inactivated virus vectors are engineered to express the target protein but have been inactivated and are thus safer since they cannot replicate, even in the immunocompromised host. Inactivated virus vector SARS-CoV-2 vaccines that display spike protein on the surface are still in the preclinical stage of development.

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DNA vaccines – DNA vaccines consist of plasmid DNA that contain mammalian expression promotors and the target gene, so that the target protein is expressed in the vaccine recipient. Large quantities of stable plasmid DNA can be generated in Escherichia coli, which is a major production advantage. However, DNA vaccines are often of low immunogenicity and need special delivery devices, such as electroporators, which limit their use. Further, DNA vaccines must reach the nucleus to be transcribed to messenger RNA (mRNA) so proteins can be generated to stimulate an immune response. SARS-CoV-2 DNA vaccines in development contain the spike protein gene as the target [22].

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RNA vaccines – RNA vaccines were the first vaccines for SARS-CoV-2 to be produced and represent an entirely new vaccine approach. Once administered, the RNA is translated into the target protein, which is intended to elicit an immune response. These vaccines are produced completely in vitro, which facilitates production. However, since the technology is new, the ability to produce large quantities of RNA vaccines has not been previously tested, and some of the vaccines must be maintained at very low temperatures, complicating storage. Several SARS-CoV-2 RNA vaccines are in late-phase clinical trials. (See ‘Vaccine candidates in late-phase studies’ below.)

VACCINE CANDIDATES IN LATE-PHASE STUDIES

The first human clinical trials of SARS-CoV-2 vaccines began in March 2020, and several phase III trials are nearing completion. Select vaccine candidates that have entered or are nearing entry into phase III trials are described here. They represent different vaccine approaches, including RNA vaccines, replication-incompetent vector vaccines, recombinant protein vaccines, and inactivated vaccines; the general features of these different platforms are described elsewhere. (See ‘Vaccine platforms’ above.)

These vaccine candidates have elicited neutralizing and cellular responses in nonhuman primates without evidence of enhanced disease [4,5,21-23]. They have demonstrated immunogenicity in early-phase human trials, most of which compared receptor-binding antibody and neutralizing antibody titers to those found in serum from patients convalescing from prior SARS-CoV-2 infection (ranging from asymptomatic to severe infection) [15]. It is difficult to compare the immunogenicity of the different vaccine candidates based on these studies, in part because of the heterogeneity of the assays employed. None of the early trials identified major safety concerns, but all vaccines elicited systemic adverse effects (fever, chills, headache, fatigue, myalgia, joint pains) in a proportion of participants, some of whom rated the effects severe enough to limit daily activity.

Results of phase III efficacy trials have been reported in press release form for several SARS-CoV-2 vaccine candidates. Although some of these data are promising, full trial reports are needed to critically assess the vaccines’ impact and safety, including effects on microbiologically confirmed SARS-CoV-2 infection (both asymptomatic and symptomatic, which could have implications for transmission). The durability of effect will also need to be evaluated over time.

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mRNA 1273 (Moderna) – This messenger RNA (mRNA) vaccine was one of the first vaccines for SARS-CoV-2 to be produced; it was developed and administered to humans within two months of publication of the SARS-CoV-2 genomic sequence. The vaccine utilizes mRNA delivered in a lipid nanoparticle to express a full-length spike protein. It is given intramuscularly in two doses 28 days apart. A phase I open-label trial demonstrated binding and neutralizing antibody responses comparable to those seen in convalescent plasma with vaccination in healthy individuals 18 to 55 years of age [32]. CD4 cell responses with a Th1 bias were also detected. Vaccination in adults older than 55 years also elicited immune responses that were comparable to those seen in the younger populations [33]. Local and systemic reactions were common, particularly after the second dose; severe systemic reactions were reported in 3 participants (21 percent) who received the highest dose studied.

According to a press release report of phase III results, mRNA-1273 had 94.1 percent vaccine efficacy in preventing symptomatic COVID-19 at or after two weeks following the second dose [34]. This effect was assessed after an analysis of 196 confirmed COVID-19 cases (11 in the vaccine group and 185 in the placebo group) among approximately 30,000 study participants. Thirty cases were severe, and all of these occurred in the placebo group. No major safety concerns were reported.

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BNT162b2 (BioNTech and Pfizer) – This mRNA vaccine is delivered in a lipid nanoparticle to express a full-length spike protein. It is given intramuscularly in two doses 21 days apart. In a phase I/II randomized, placebo-controlled, observer-blind dose escalation study in healthy adults 18 to 85 years of age, binding and neutralizing antibody responses were demonstrated that were comparable to those in convalescent plasma from patients who had asymptomatic or moderate SARS-CoV-2 infection [35]. Responses in participants ≥65 years old were generally lower than in younger subjects, but still comparable to titers in convalescent plasma. Systemic adverse effects were dose dependent and were more common after the second dose; severe systemic effects were reported in a small number of participants younger than 55 years but not in older participants.

According to a press release report of phase III results, this vaccine had 95 percent efficacy in preventing symptomatic COVID-19 at or after day 7 following the second dose [36]. This effect was assessed after an analysis of 170 confirmed COVID-19 cases (8 in the vaccine group and 162 in the placebo group) among nearly 40,000 participants. Nine of the 10 severe cases occurred in the placebo group. The efficacy among adults >65 years old was >94 percent.

In December 2020, BNT162b2 was approved for use in the United Kingdom [37].

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NVX-CoV2373 (Novavax) – This is a recombinant protein nanoparticle vaccine composed of trimeric spike glycoproteins and a potent Matrix-M1 adjuvant. The vaccine is given intramuscularly in two doses 21 days apart. In a phase I/II randomized, placebo-controlled trial of healthy individuals <60 years old, the adjuvanted vaccine induced high binding and neutralizing responses, comparable to those in convalescent plasma from patients who had been hospitalized with COVID-19 [38]. CD4 cell responses with a Th1 bias were also detected. Approximately 6 percent of participants experienced severe systemic effects (mainly fatigue, headache, myalgias, and/or malaise) following the second dose.

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ChAdOxnCoV-19/AZD1222 (University of Oxford, AstraZeneca, and the Serum Institute of India) – This vaccine is based on a replication-incompetent chimpanzee adenovirus vector that expresses the spike protein. It is given intramuscularly and is being evaluated as a single dose or two doses 28 days apart. In a single-blind, randomized controlled phase I/II trial in healthy individuals 18 to 55 years old, in which most of the vaccine recipients received a single dose and a small cohort received an additional booster dose, neutralizing antibody titers 28 days after the last dose were comparable to those detected in convalescent plasma [39]. The levels of antibody titers achieved were higher following two doses; and subsequent studies are evaluating the two-dose regimen. Cellular immune responses were also detected. Fatigue, headache, and fever were relatively common after vaccine receipt and were severe in up to 8 percent of recipients. In a study that included older vaccine recipients (>70 years), the vaccine was better tolerated in this age group than in younger adults and resulted in similar antibody responses after the second dose [40]. Larger phase III trials of this vaccine were paused when a trial participant in the United Kingdom developed transverse myelitis, but these trials have since resumed.

According to a press release report of interim phase III results, this vaccine had 70 percent efficacy in preventing symptomatic COVID-19 at or after 14 days following the second dose [41]. This effect was assessed after an analysis of 131 confirmed COVID-19 cases among over 20,000 participants and represents a combined analysis of two different dosing regimens. No hospitalizations or severe cases were documented in the vaccine groups; however, the rate of these outcomes in the control groups was not reported.

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Ad26.COV2.S (Janssen) – This vaccine is based on a replication-incompetent adenovirus 26 vector that expresses a stabilized spike protein. It is given intramuscularly and is being evaluated as a single dose. An unpublished report from a phase I/II randomized, double-blind, placebo controlled trial described high rates of neutralizing and binding antibodies after a single vaccine dose in healthy individuals 18 to 85 years old; these responses overlapped with but were slightly lower than those in convalescent plasma [42]. Fewer than one percent reported severe systemic reactions. CD4 cell responses with a Th1 bias were also detected. Adenovirus 26 vectors are used in an Ebola vaccine that is licensed in Europe and in RSV, HIV, and Zika vaccine candidates. Baseline seroprevalence to adenovirus 26 is low in North America and Europe; it is moderately high in sub-Saharan Africa and Southeast Asia, although most seropositive individuals have low neutralizing titers [43]. Nonhuman primate studies suggest that these low titers do not suppress responses to adenovirus 26 vector vaccines.

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Ad5-based COVID-19 vaccine (CanSino Biologics) – This vaccine is based on a replication-incompetent adenovirus 5 vector that expresses the spike protein. It is given as a single intramuscular dose. In early clinical trials, it was immunogenic in healthy adults at 28 days with only mild to moderate local and systemic reactions [44]. However, both pre-existing immunity to adenovirus 5 and older age were associated with lower titers of binding and neutralizing antibodies following vaccination; this may limit its utility in locations where pre-existing immunity is prevalent. The vaccine has been licensed in China for limited use by the military [45]. Prior studies of adenovirus 5 vector HIV vaccine candidates identified an increased risk of HIV acquisition among male vaccine recipients who were uncircumcised and seropositive for adenovirus 5 at baseline [46]. It is uncertain whether these observations are relevant for adenovirus 5 SARS-CoV-2 vaccines.

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Sputnik V (Gamaleya Institute) – This is a vaccine developed in Russia that uses two replication-incompetent adenovirus vectors that express a full-length spike glycoprotein. The vaccine is given intramuscularly as an initial adenovirus 26 vector dose followed by an adenovirus 5 vector boosting dose 28 days later. In an open-label, nonrandomized phase I/II trial, the vaccine was associated with mild to moderate local and systemic reactions, but SARS-CoV-2 humoral and cellular immune responses were detected in the participants [47]. This vaccine was licensed in Russia prior to completion of any efficacy trials. Russian officials reported a 91.4 percent efficacy rate following interim analysis of a phase III trial; however, the validity of this estimate is questionable because it is based on only 39 cases [48].

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BBIBP-CorV (Sinopharm) – This is an inactivated vaccine based on a SARS-CoV-2 isolate from a patient in China; it has an aluminum hydroxide adjuvant. The vaccine is given intramuscularly in two doses 28 days apart. In phase I/II placebo-controlled randomized trials of healthy individuals 18 to 80 years old, all recipients of two vaccine doses developed neutralizing and binding antibodies; no severe reactions were reported [49,50].

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CoronaVac (Sinovac) – This inactivated SARS-CoV-2 vaccine was developed in China; it has an aluminum hydroxide adjuvant. The vaccine is given intramuscularly in two doses 28 days apart. In a phase I/II randomized, placebo-controlled trial, the vaccine appeared safe and immunogenic in healthy individuals aged 18 to 59 years [51].

STEPS TO VACCINE AVAILABILITY AND DELIVERY

Establishing efficacy — Results of phase III trials are necessary to assess vaccine efficacy for preventing COVID-19. Several such trials are underway, and results from some have been reported in press release form or are anticipated by the end of 2020. The US Food and Drug Administration (FDA) has provided minimal efficacy criteria for licensure; vaccine efficacy should be at least 50 percent, with a lower bound of a 95% confidence interval of 30 percent [52]. The World Health Organization (WHO) has proposed the same minimal efficacy targets [53]. The primary clinical outcome is generally microbiologically confirmed symptomatic COVID-19 [52]. Severe COVID-19 is also an additional endpoint.

Many SARS-CoV-2 vaccine efficacy trials are enrolling over 30,000 individuals in each study (generally divided equally between vaccine and comparator groups), which is the estimated number necessary to sufficiently determine vaccine efficacy over a follow-up of six months. This time frame depends on the infection rate in the control group; the higher the infection rate, the less time is needed to determine vaccine efficacy. Each trial targets a defined number of detected cases, and when that number of cases has been reported, efficacy will be assessed. Most of the trials have interim efficacy determinations, as had been reported for two mRNA vaccines. (See ‘Vaccine candidates in late-phase studies’ above.)

Prevaccination screening to identify SARS-CoV-2-naïve participants for trial enrollment is not recommended, as it is unlikely to be used in clinical practice, and establishing vaccine safety in individuals with prior infection is important [52]. The US FDA strongly encourages that trials enroll populations that have been disproportionately affected by the COVID-19 pandemic, in particular ethnic minorities.

It is hoped that results from vaccine efficacy trials can be used to establish standardized functional antibody responses that correlate with protection from disease, called a correlate of protection [54]. This usually entails measuring antibody titers before and after vaccination and identifying an association between responses below a certain threshold and vaccine failure. If such correlates are established, it may be possible to license vaccines based on the achievement of these serologic benchmarks and not require each vaccine to be tested in large clinical efficacy trials. This is especially relevant for candidate vaccines that will not have already entered efficacy trials by the time a SARS-CoV-2 vaccine is available and in use, as it will then be logistically and ethically challenging to conduct large placebo-controlled efficacy trials for new vaccines.

Licensing a vaccine — In the United States, the FDA makes decisions on vaccine licensure once phase III trials are concluded and demonstrate safety and efficacy according to the minimal efficacy criteria (see ‘Establishing efficacy’ above). In making this determination, the FDA relies on guidance from the Vaccines and Related Biologic Products Advisory Committee (VRBPAC), a standing advisory group of experienced clinicians, vaccine experts, epidemiologists, and other subject matter experts. The FDA poses focused questions to the VRBPAC that relate to both vaccine efficacy and vaccine safety. All the adverse events reported in clinical trials are comprehensively presented and discussed with the committee. Incorporating the advice of the VRBPAC, the FDA determines whether the vaccine will be licensed and what limitations will be placed on the licensure. Similar approaches are taken by regulatory bodies in Canada and European countries for the licensure of their vaccines.

In addition to the traditional process to issue a license for a vaccine, the FDA can more rapidly make vaccines available in an emergency situation. This is called an Emergency Use Authorization (EUA) and is designed to make products available during public health emergencies. Under these circumstances, the FDA deems that the product “may be effective” and that benefits are likely to outweigh the risks [55]. The FDA has indicated that it will only issue an EUA for a SARS-CoV-2 vaccine if there is substantial evidence of safety and effectiveness, which includes meeting the prespecified efficacy criteria defined for the primary endpoint [56]. A median of two months of follow-up for half of the vaccine participants following vaccine receipt is also required. For vaccines available under EUA, clinicians are obliged to inform potential recipients that the vaccine is not licensed, why it is not licensed, and what information the FDA is waiting for before granting a full license. It is not necessary, however, for recipients to sign informed consent documents.

Vaccine manufacturing and storage — Given the constrained timeline for testing and the need for rapid deployment of the SARS-CoV-2 vaccines, several vaccine producers have started commercial production prior to the availability of phase III trial efficacy data so that the vaccine could be quickly made available for use as soon as it is approved. This is unusual, since vaccine production facilities for widespread use of vaccines are typically not developed until after vaccine efficacy has been established, to minimize financial risk.

For SARS-CoV-2 vaccines, manufacturing capabilities have been enhanced by the infusion of government funds. As an example, the United States government has agreed to finance production of hundreds of millions of doses of promising vaccine candidates prior to completion of the phase III trials [57]. This reduces manufacturer risk if the vaccine does not meet licensure criteria.

Technical requirements for storage and handling may pose operational challenges for widespread distribution of SARS-CoV-2 vaccine candidates. As an example, some mRNA vaccines require ultra-cold storage in specialized freezers. The need for vials used to hold the vaccines may also pose supply chain issues.

Key issues for vaccination policy — Vaccinations, not vaccines, prevent infections and save lives. Once a SARS-CoV-2 vaccine is licensed for use in the United States, several questions must be addressed. These are outlined below and include:

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Who should receive the vaccine (and who should not)

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High-priority groups for vaccination

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Immunization schedule and need for booster doses

Systems need to be in place to provide access to vaccines, and barriers to access, such as cost, need to be removed. Ongoing monitoring of vaccine effectiveness and safety is critical for evaluating issues such as waning immunity, risk for vaccine failure, and vaccine-related adverse events, particularly rare events that were not detected in pre-licensure trials. (See ‘Post-licensure monitoring’ below.)

Estimations of the burden of causally vaccine-related adverse events can then be weighed against the benefits of the vaccine to determine if any changes in recommendations are warranted. Disease surveillance is crucial to determine who continues to get disease, risk factors for that disease, and the role of vaccine failure versus failure to vaccinate in disease occurrence.

Allocation priorities — Following availability of one or more SARS-CoV-2 vaccines, time will be needed to ramp up manufacturing to provide sufficient quantities for universal vaccination. Until that has been achieved, it is essential that deployment of limited vaccine supplies be equitable and efficient. Several expert organizations have released guidance documents for vaccine allocation approaches that maximize the individual and societal benefits of vaccination [58-60]:

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In the United States, the National Academies of Sciences, Engineering, and Medicine (NASEM) proposed a four-phase allocation framework (table 1) based on the ethical principles of maximum benefit, equal concern, and health inequity mitigation and on the procedural principles of fairness, transparency, and being evidence-based [58]. It prioritizes vaccination according to risks of acquiring infection, severe morbidity and mortality, negative societal impact (eg, if essential critical societal functions depend on an individual or groups of individuals), and transmission to others. The document suggests that initial vaccine supplies be allocated to individuals with the highest risks across these categories (ie, high-risk frontline health care workers, first responders, those with comorbidities highly associated with severe COVID-19, and older individuals in congregate settings). As vaccination capacity expands, allocation will be broadened to populations with progressively lower risk.

A vaccine allocation planning tool has been developed to assess how many vaccines would be needed per state for each priority population within this allocation framework.

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The Advisory Committee on Immunization Practices (ACIP) of the United States Centers for Disease Control and Prevention (CDC), a body that makes formal recommendations for vaccine administration, has considered a similar framework for vaccine allocation with the with the primary goals of maximizing the reduction in death and serious disease, preserving societal function, reducing the burden of disease among those already facing disparities, and improving health and well-being. It voted to recommend that the first vaccine supplies be allocated to health care personnel and long-term care facility residents, similar to the NASEM recommendations; these populations account for approximately 24 million individuals in the United States [61]. Other priority groups that the ACIP had previously identified and that will be included in subsequent phases of vaccine distribution are workers in essential and critical industries, individuals at high risk for severe COVID-19 due to underlying medical conditions, and individuals 65 years and older [59].

Both frameworks acknowledge that in the United States and elsewhere, certain minority populations, including Black, Latino, and Indigenous populations, have been disproportionately impacted by the pandemic because of structural inequities and social determinants of health. They emphasize that, within each risk group, equitable vaccine allocation to these and other vulnerable populations should be a priority.

The framework proposed by the WHO also takes into account global equity concerns, including assurance of vaccine access to low- and middle-income countries [60].

Role of the ACIP — In the United States, the Advisory Committee on Immunization Practices (ACIP) of the CDC plays a major role in determining vaccination recommendations following FDA licensure of a vaccine [62]. The ACIP covers recommendations for children, adolescents, and adults and takes into account disease epidemiology, burden of disease, vaccine efficacy and effectiveness, vaccine safety, the quality of the evidence reviewed, analyses, and implementation issues [63]. Since 1995, the ACIP, American Academy of Pediatrics, American Academy of Family Physicians, American College of Physicians, American College of Obstetricians and Gynecologists, and other expert organizations have worked together to develop and annually update vaccination schedules for children, adolescents, and adults [64]. The ACIP also prioritizes vaccine use in the setting of shortages. Once approved by the CDC director, the ACIP recommendations are published in the Morbidity and Mortality Weekly Report and become official CDC immunization policy.

Vaccine reimbursement — In the United States, SARS-CoV-2 vaccines will be free of charge for any individual for whom the ACIP recommends vaccination [65]. Vaccine providers can get administration costs reimbursed by public or private insurers, or for uninsured patients, by the Health Resources and Services Administration’s Provider Relief Fund [66].

Combating vaccine hesitancy — Vaccine hesitancy presents a major obstacle to achieving vaccination coverage that is broad enough to result in herd immunity and slow community transmission. In general, vaccine hesitancy has become more common worldwide and was cited by the WHO as a top 10 global health threat in 2019 [67]. With SARS-CoV-2 vaccines, the accelerated nature of development, which has led to perceptions that corners are being cut with regard to safety assessments, and misinformation about the severity of COVID-19 may contribute further to concerns or skepticism about safety and utility among vaccine-hesitant individuals. Efforts to optimize SARS-CoV-2 vaccine uptake should identify reasons for and characteristics associated with vaccine refusal and use that information to tailor approaches to individuals and populations.

Willingness to accept a SARS-CoV-2 vaccine varies by country. In an online survey of 13,426 participants from 19 countries who were asked if they would accept a “proven, safe and effective vaccine,” 72 percent overall said they completely or somewhat agreed [68]. The highest proportion of positive responses were from China, South Korea, and Singapore (over 80 percent), whereas the lowest were from Russia (55 percent).

In the United States, in a survey of 991 individuals conducted in April 2020, 58 percent reported that they would accept a SARS-CoV-2 vaccine, 32 percent were unsure, and 11 percent would decline vaccination [69]. Vaccine hesitancy was more likely among those who were younger (<60 years old), were Black, had not obtained a college degree, and had not received influenza vaccine in the prior year. Among those who said they would decline the vaccine, the most common reasons were antivaccine beliefs, including the belief that they are not at risk for COVID-19 (57 percent), and lack of trust (33 percent). Among those who were unsure, the common reasons were specific concerns about the SARS-CoV-2 vaccine itself (57 percent) and the need for more information (25 percent).

Vaccine acceptance might increase if vaccines are confirmed to be highly effective; in another United States survey, an increase in efficacy of the proposed vaccine from 50 to 90 percent was associated with a 10 percent higher mean willingness to receive it [70].

Based on evidence from other vaccines, health care providers can improve vaccine acceptance in individual patients by making direct recommendations for vaccination, identifying concerns, educating patients on vaccine risks and benefits, and dispelling misconceptions about the disease and the vaccine. (See “Standard childhood vaccines: Parental hesitancy or refusal”, section on ‘Target education’ and “Human papillomavirus vaccination”, section on ‘Strategies to improve vaccine coverage’.)

Addressing special populations

Children — Vaccine licensure will only include children once the safety and immunogenicity of the vaccine has been studied in them. Such studies are underway in older children and are planned in younger children. COVID-19 is generally less severe in children than adults; nevertheless, the risk of the multisystem inflammatory syndrome in children (MIS-C) following acute infection, the risk of severe disease in children with underlying medical conditions, and the general desire to prevent COVID-19 in children remain compelling reasons for vaccine studies in children [71]. Given the hypothesis that MIS-C is associated with immune dysregulation precipitated by SARS-CoV-2 infection, immune-related side effects following vaccination in children must be closely monitored. (See “Coronavirus disease 2019 (COVID-19): Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis”.)

Most vaccines for children are delivered by private health care providers, although many are purchased using federal or other government funds. The Vaccines for Children (VFC) program is an entitlement program for all ACIP-approved vaccines for eligible children through 18 years of age [72,73]. Eligible children include those on Medicaid, those who are completely uninsured, and American Indian/Alaskan Natives. Approximately 50 percent of children are covered by the VFC. In addition, federal grants to states can be used to purchase vaccines to cover other children. Since SARS-CoV-2 vaccines will be free to all persons for whom the vaccines are recommended, these funding mechanisms may be used with the SARS-CoV-2 vaccines that are licensed in children in addition to other funding sources.

Pregnant women — Vaccine studies are also planned in pregnant women, with data and safety monitoring boards that include obstetricians experienced in vaccine studies. Since organogenesis occurs in the first trimester of pregnancy, vaccine studies will begin in healthy pregnant women in the second and third trimesters of pregnancy.

POST-LICENSURE MONITORING

Although SARS-CoV-2 vaccines will receive an emergency use authorization or be licensed based on trials conducted in tens of thousands of participants, they will be recommended for hundreds of millions of individuals once available. Thus, when used to this extent, efficacy questions that were not addressed in clinical trials will need to be monitored, and safety issues that were not initially evident may emerge.

Outstanding efficacy uncertainties — Phase III clinical trials may not answer several efficacy questions related to SARS-CoV-2 vaccination. These include:

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Duration of protection from disease

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Potential need for and timing of additional booster doses

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Effectiveness in subpopulations not evaluated in the clinical trials

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Impact on community transmission (ie, herd immunity)

Ongoing follow-up of trial participants and additional observational studies are necessary to address these issues.

Comprehensive surveillance systems are also needed to detect and determine the impact of the vaccines on COVID-19 burden in the post-vaccine era. Continued high rates of infection despite vaccine availability may reflect the failure to vaccinate or vaccine failure. If the former, measures to enhance vaccine uptake should be explored, and vaccination recommendations may warrant broadening if substantial numbers of cases occur in groups for whom vaccine is not recommended. If ongoing infection is related to low vaccine effectiveness, assessment should focus on potential risk groups for vaccine failure and whether additional vaccine doses or alternative schedules could reduce that risk.

Ongoing safety assessment — Adequately assessing vaccine safety is critical to the success of immunization programs. Although existing comprehensive systems to monitor vaccine safety are in place, they are being enhanced for the rollout of the SARS-CoV-2 vaccine program. It is particularly important to identify rare adverse events that are causally related to vaccine administration and assess their incidence and risk factors to inform potential vaccine contraindications.

In the United States, there are several systems in place to assess safety in the post-licensure setting; some are passive (ie, rely on others reporting the event) and others are active (ie, review databases or conduct studies to identify events) [74]. These include the Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system in which providers, parents, and patients report adverse events. VAERS is intended to raise hypotheses about whether receipt of a vaccine could cause the adverse event rather than evaluate causation. The Vaccine Safety Datalink (VSD) is a collaborative project between the United States Centers for Disease Control and Prevention’s (CDC’s) Immunization Safety Office and eight health care organizations to actively monitor the safety of vaccines and conduct studies about rare and serious post-vaccination adverse events. The Clinical Immunization Safety Assessment project (CISA) is a national network of vaccine safety experts from the CDC’s Immunization Safety Office, seven academic medical research centers, and subject matter experts, and it provides a comprehensive vaccine safety public health service to the nation.

In addition, specific post-licensure vaccine safety systems are being implemented in preparation for the introduction of SARS-CoV-2 vaccines, similar to those established during the 2009 H1N1 influenza pandemic [75,76]. These systems will be coordinated through the CDC and will enlist multiple other health care groups to provide ongoing data on vaccine safety. These systems and information sources add an additional layer of safety monitoring [77,78].

V-SAFE is a new smartphone-based health checker for people who have received a SARS-CoV-2 vaccine. The CDC will send text messages and web-based surveys to vaccine recipients through V-SAFE to check in regarding health problems following vaccination. The system will also provide telephone follow-up to anyone who reports clinically significant adverse events.

Enhanced reporting through National Healthcare Safety Network (NHSN) sites – A monitoring system for health care workers and long-term care facility residents that reports to the VAERS.

Monitoring of larger insurer/payer databases through the US Food and Drug Administration – A system of administrative and claims-based data for surveillance and research.

Since most vaccine-preventable diseases are transmitted person-to-person, effective vaccination not only protects the recipient but also indirectly protects others who cannot be vaccinated or do not respond adequately by preventing another source for transmission (“herd immunity”) [79]. Therefore, if someone is injured by vaccine, society owes that person compensation. This is the basis for the National Vaccine Injury Compensation Program (NVICP) [80]. This program also reduces liability for the vaccine provider and the manufacturer, since it is a no-fault alternative to the traditional legal system for resolving vaccine injury claims. With SARS-CoV-2 vaccines, another compensation system called the Countermeasures Injury Compensation Program (CICP) may be used [81].

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See “Society guideline links: Coronavirus disease 2019 (COVID-19) – International public health and government guidelines” and “Society guideline links: Coronavirus disease 2019 (COVID-19) – Guidelines for specialty care” and “Society guideline links: Coronavirus disease 2019 (COVID-19) – Resources for patients”.)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see “Patient education: Coronavirus disease 2019 (COVID-19) overview (The Basics)” and “Patient education: Coronavirus disease 2019 (COVID-19) and pregnancy (The Basics)” and “Patient education: Coronavirus disease 2019 (COVID-19) and children (The Basics)”)

SUMMARY AND RECOMMENDATIONS

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Vaccines to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are considered the most promising approach for controlling the pandemic. SARS-CoV-2 vaccine development is occurring at an unprecedented pace. (See ‘Overview of vaccine development’ above.)

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Nonhuman primate studies and epidemiologic human studies suggest that SARS-CoV-2 infection results in the development of functional neutralizing antibodies that are associated with protection from reinfection. These observations support the concept that a vaccine that elicits neutralizing antibodies could also protect against subsequent infection. Neutralizing antibody and Th1-polarized cellular immune responses are thought to be important in reducing the risk of vaccine-enhanced disease. (See ‘Immunologic basis for SARS-CoV-2 vaccination’ above and ‘Antigenic target’ above.)

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The primary antigenic target for SARS-CoV-2 vaccines is the large surface spike protein (figure 1), which binds to the angiotensin-converting enzyme 2 (ACE2) receptor on host cells and induces membrane fusion (figure 2). (See ‘Antigenic target’ above.)

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SARS-CoV-2 vaccines are being developed using several different platforms (figure 3). Some of these are traditional approaches, such as inactivated virus or live attenuated virus platforms, some are newer approaches, such as recombinant proteins and vector vaccines, and some have never been previously employed in a licensed vaccine, such as RNA and DNA vaccines. (See ‘Vaccine platforms’ above.)

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Several vaccine candidates have demonstrated immunogenicity without major safety concerns in early-phase human trials. Two mRNA vaccine candidates have also been reported to have approximately 95 percent vaccine efficacy in preventing laboratory-confirmed symptomatic coronavirus disease 2019 (COVID-19). (See ‘Vaccine candidates in late-phase studies’ above.)

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In the United States, in addition to the traditional process to license a vaccine, the Food and Drug Administration can make vaccines that meet specific safety and efficacy criteria available more rapidly through an emergency use authorization (EUA). For vaccines available under EUA, clinicians must inform potential recipients that the vaccine is not licensed, why it is not licensed, and what information the FDA is waiting for before granting a full license; a signed inform consent document is not required. (See ‘Licensing a vaccine’ above.)

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Deployment of the limited vaccine supplies that will be initially available should be equitable and efficient. Several expert organizations have provided guidance for vaccine allocation approaches that maximize the individual and societal benefits of vaccination. These generally prioritize workers in essential industries (including health care) and individuals at risk of severe infection (table 1). (See ‘Allocation priorities’ above.)

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Following availability and widespread uptake of SARS-CoV-2 vaccines, efficacy issues that were not addressed in clinical trials will need to be evaluated, including the duration of protection and potential need for additional doses, effectiveness in subpopulations not included in trials, and impact on community transmission. Safety issues that were not initially evident may also emerge. In the United States, existing active and passive monitoring systems are being enhanced to closely assess safety of SARS-CoV-2 vaccines. (See ‘Post-licensure monitoring’ above.)

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