The failure to control the spread and resurgence of coronavirus disease 2019 (COVID-19) through nonpharmacological means in the United States and around the world has accelerated the need for vaccines to prevent and help mitigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, the cause of this disease. Worldwide, there are more than 200 candidate vaccines in different stages of development,1 44 of which are in clinical trials or have been approved for use in other countries (ie, China and Russia). In the US, five candidate COVID-19 vaccines have entered or are about to enter Phase III clinical trials, none of which include children, except for one that has recently expanded enrollment to adolescents as young as age 12 years.2
SARS-CoV-2 is a positive sense, single-stranded, enveloped virus within the family Coronaviridae closely related to SARS-CoV-1, the confirmed cause of the 2003 SARS (severe acute respiratory syndrome) pandemic.3 Five other members of this family cause disease in humans. Human coronaviruses 229E, NL63, OC43, and HKU1 are causes of the common cold. Middle East respiratory syndrome coronavirus is the cause of Middle East respiratory syndrome (MERS).
Host Immune Responses to Sars-Cov-2 Infection
Coronaviruses use a large surface spike (S) protein to bind to a cellular receptor, via its receptor-binding domain (RBD), leading to fusion of the viral and cellular membranes. In the case of SARS-CoV-2, the receptor is angiotensin-converting enzyme 2. Antibodies directed to the S protein and, in particular, to the RBD inhibit binding/infection and neutralize the virus.
Natural infection with SARS-CoV-2 results in the development of antibodies directed to the S protein, including its RBD, that neutralize the virus. The humoral immune response to SARS-CoV-2 infection generates type-specific immunoglobulin (Ig) M, IgG, and IgA antibodies. Several peculiarities exist in the host humoral response to COVID-19.4 The canonical sequence of the appearance of antibody isotypes, IgM followed by IgG, may not occur in all patients. Some people demonstrate the simultaneous appearance of IgM and IgG antibodies, whereas others have reversal in temporal appearance of these with IgG preceding IgM. Further, the magnitude of the immune response to infection varies among people with symptomatic versus asymptomatic infection such that severity of illness is not directly correlated with serum antibody levels. Additionally, within each of the groups there is significant variation in the magnitude of antibody concentration. Type-specific IgM and IgG antibodies provide systemic immunity, whereas secretory IgA provides mucosal immunity. In patients that recovered from SARS-CoV-2 infection, specific CD8+ and CD4+ T cells were identified in approximately 70% and 100% of patients, respectively.5
The duration of immunity after natural COVID-19 infection is unknown. At least one report suggests that humoral immunity against SARS-CoV-2 may not be long-lasting in people who have recovered from mild illness.6 In contrast, a study comprised of more than 90% of its participants who were patients hospitalized for COVID-19 documented little decrease in anti-S neutralizing antibodies for 75 days after symptom onset.7 A study of protective immunity to seasonal coronaviruses after infection fails to support long-lived immunity.8 In one long-term study, re-infections with the same seasonal coronavirus types occurred frequently 12 months after the infection.9 Well-documented reports of SARS-CoV-2 reinfection are beginning to appear.10
The Process for Developing Covid-19 Vaccine Candidates
COVID-19 vaccine development has been informed and accelerated by knowledge gained from previous efforts to develop vaccines against SARS-CoV-1 and MERS. Pre-clinical studies for both known infections identified the S protein as the antigenic target. SARS-CoV-1 Phase I clinical trials documented the immunogenicity of the S protein in humans.11–13 This understanding allowed for the design of an RNA construct encoding the protein sequence for the S protein of SARS-CoV-2 within 48 hours of the complete genomic sequence of this novel virus being made available.13
The vaccine development process for COVID-19 vaccines in the US has been accelerated under Operation Warp Speed (OWS), a partnership among the Department of Health & Human Services (HHS), including the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), the Biomedical Advanced Research and Development Authority, and the Department of Defense. OWS engages the pharmaceutical industry and additional federal agencies to coordinate existing HHS-wide efforts. This includes the NIH's Accelerating COVID-19 Therapeutic Interventions and Vaccines public-private partnership. The purpose of OWS is to accelerate vaccine development while maintaining standards for safety and efficacy14,15 through this public-private partnership.
Using knowledge gained from the study of other coronaviruses known to infect humans, the COVID-19 vaccine development timeline has been compressed from the typical 10 to 15 years to 10 to 18 months. This has been accomplished by being able to greatly minimize the pre-clinical vaccine development phase, specifically as a result of prior knowledge and clinical or human testing phases of vaccine development by overlapping the three phases of vaccine trials.16 Additionally, rather than waiting on vaccine licensure to begin large-scale production, concurrent production of vaccines being studied in Phase III clinical trials assures that some vaccine supply will be available immediately after the US Food and Drug Administration's (FDA) approval of a new vaccine and the CDC's Advisory Committee on Immunization Practices (ACIP) recommendation for its use.
All vaccines entering Phase III clinical trials have demonstrated efficacy for the prevention of SARS-CoV-2 infection in animal models. Additionally, no safety signals of concern were observed during study Phases I and II. It is important to note that although the vaccine timeline has been compressed, vaccine safety remains a central and leading criterion for the development of COVID-19 vaccines as indicated by statements from pharmaceutical companies, the FDA, and the CDC.
Platforms Being Used with Covid-19 Vaccine Candidates
The development of COVID-19 vaccines worldwide has relied on one of six platforms: RNA, replication-incompetent (nonreplicating) viral vector, recombinant protein, inactivated, live-attenuated, and DNA vaccines.16 This portion of the article focuses on those platforms used for development of COVID-19 vaccines under OWS for use in the US and currently in Phase III clinical trials or imminently beginning Phase III.
RNA vaccines are a novel development among the platforms being used, as no licensed RNA-based vaccine is currently available. In this platform, messenger RNA (mRNA) encoding the protein antigen (immunogen) of interest, encapsulated within lipid nanoparticles, are delivered to cells. The cells express the antigen, which then stimulates the host immune system to produce antibodies to it. The lipid encapsulated mRNA is delivered to the host by injection. Thus, these vaccines are unlikely to induce mucosal immunity.
The advantages of this platform are that biosafety level III (BSL3) research/production facilities are not necessary to produce the vaccine because viable SARS-CoV-2 is not required. The entire production process can be performed in vitro. However, mRNA vaccines require cold storage, which may complicate their ultimate delivery.
The first candidate–COVID-19 vaccines to enter Phase III clinical trials in the US were mRNA vaccines. The biotechnology company Moderna (Cambridge, MA), in collaboration with the National Institute of Allergy and Infectious Diseases, developed an mRNA vaccine that expressed the S protein of SARS-CoV-2 (mRNA-1273). The vaccine began a randomized, observer-blinded, placebo-controlled Phase III clinical trial on July 27, 2020 (NCT04470427).15,17 The vaccine is administered in two doses at 0 and 28 days by intramuscular injection. The trial will enroll at least 30,000 participants, age 18 to 56 years. Interim analysis of its Phase III study demonstrated that mRNA-1273 had an efficacy of 94.5%. No safety concerns were identified by the data safety monitoring board. Lastly, the vaccine has been shown to be stable for 30 days at 2° to 8°C.18
A second mRNA SARS-CoV-2 vaccine in Phase III trials is Pfizer (New York, NY) and BioNTech's (Mainz, Germany) BNT162b2 vaccine. The mRNA expresses the SARS-CoV-2 S protein. This vaccine also began randomized, observer-blinded, placebo-controlled Phase III clinical trials on July 27, 2020 (NCT04368728).15,19 The vaccine is administered by intramuscular injection in two doses on days 0 and 21. The trial will enroll approximately 44,000 participants, age 12 to 86 years. Final efficacy analysis has demonstrated it to be 95% effective 7 days after the second dose.20 This vaccine will also require cold storage, but at a much lower temperature of −70°C.
Replication-Incompetent (Nonreplicating) Viral Vector Vaccines
Nonreplicating viral vector vaccines use a virus that has been rendered incapable of replicating in vivo and engineered to express the antigen of interest. Once delivered intramuscularly, the vector enters the vaccinee's cells and expresses the antigen. The host immune system then mounts an immune response to it.
Multiple viral vectors have been developed for use in this platform, which offers several advantages. Without any viable SARS-CoV-2 virus, BSL3 facilities are not required. Extensive experience exists for the use of this platform.
In late August 2020, AstraZeneca (Cambridge, United Kingdom) launched their randomized, double-blind, placebo-controlled Phase III clinical trial (NCT04516746) of a COVID-19 vaccine (AZD1222) based on the replication-defective viral vector platform.15,21 This vaccine is a collaboration between Oxford University's Jenner Institute and AstraZeneca. The vaccine uses a nonreplicating chimpanzee adenovirus vector (ChAdOx1) to deliver the S protein of SARS-CoV-2 to induce an immune response. Participants include 50,000 people, age 18 to 130 years ( https://clinicaltrials.gov/ct2/show/NCT04516746); they are being enrolled to receive this vaccine delivered intramuscularly in two doses at days 0 and 28.
Janssen Pharmaceutical Company (Beerse, Belgium) initiated a randomized, double-blind, placebo-controlled Phase III trial of its candidate–COVID-19 vaccine in late September 2020 (NCT04505722).15,22 The vaccine uses the adenovirus 26 replication-defective vector to deliver and express the SARS-CoV-2 S protein. The company has used similar technology to develop a vaccine against Ebola virus. The trial will enroll 60,000 participants age 18 years and older. Uniquely, this vaccine requires a single intramuscular dose, unlike the previously described candidate–COVID-19 vaccines.
Recombinant Protein Vaccines
These vaccines use recombinant proteins that have been produced in various expression systems (eg, insect cells, mammalian, yeast, plants). The vectors used to deliver the gene encoding the protein of interest are specific to each expression system. The recombinant protein can be produced in large scale, purified, and used as the immunogen. Multiple vaccines for human diseases use recombinant proteins (eg, hepatitis B vaccine, influenza vaccine, human papillomavirus vaccine), so extensive experience exists using this platform.
Novavax's (Gaithersburg, MD) COVID-19 protein subunit vaccine candidate, NVX-CoV2373, uses the insect virus vector baculovirus to infect insect cells (baculovirus Spodoptera frugiperda system) and deliver the gene encoding for the full-length SARS-CoV-2 spike protein including its transmembrane domain.23 Insect cells that are infected produce the recombinant protein that is used as the immunogen in the vaccine. In addition, this vaccine uses a saponin-based adjuvant, Maritx-M1, derived from the tree Quillaja saponaria Molina.24 As presented at the CDC ACIP meeting in Atlanta, GA, on October 30, 2020, this vaccine has not yet entered Phase III clinical trials (NCT04611802) but has completed enrollment in its Phase I/II study (NCT04368988).25 The vaccine will require two doses given at 0 and 21 days by intramuscular injection.
Efficacy and Safety of Covid-19 Vaccine Candidates
The FDA has issued guidelines for the development and licensure of vaccines to prevent COVID-19 disease.26 In particular, the primary efficacy statistical endpoint estimate must be at least 50%. This efficacy benchmark would somewhat compare with that of influenza vaccines. COVID-19 vaccines with 50% efficacy could reduce the incidence of COVID-19 in people receiving the vaccine as well as possibly prove useful in developing herd immunity. Also, the impact of the vaccine on severe COVID-19 disease and symptomatic/asymptomatic SARS-CoV-2 infection must be considered as primary or secondary endpoints.
In addition to efficacy, the FDA has placed safety evaluation of COVID-19 vaccines as paramount in the assessment for licensure.26 The evaluation for safety should not be different from any other preventive vaccines for infectious diseases. This applies to vaccine development during all three clinical phases. The safety elements being monitored include (1) solicited local and systemic adverse events observed for at least 7 days post each vaccination; (2) unsolicited adverse events collected for a minimum of 21 to 28 days after each vaccination; (3) serious and medically attended adverse events monitored for at least 6 months after the completion of all study vaccinations. For those vaccine platforms using novel antigens, a longer safety period of observation may be warranted, and all pregnancies for which the date of conception is prior to vaccination or within 30 days after vaccination should be observed for outcome (ie, pregnancy loss, stillbirth, congenital anomalies). In addition, an independent data safety monitoring board (DSMB) is recommended to be created for each vaccine. The DSMB functions as a monitor of the overall clinical trial to ensure the integrity and validity of the study data from all participants.
Vaccine-Enhanced Disease Syndromes
Vaccine-enhanced disease is of particular concern in the development of COVID-19 vaccines. Two syndromes have been described: antibody-dependent enhancement (ADE) and vaccine-associated enhanced respiratory disease (VAERD).27 Disease associated with ADE is a result of Fc-mediated enhancement of infection. Virus-antibody complexes bind by way of the Fc portion of the antibody to Fc receptor bearing cells and trigger internalization of the virus and infection. ADE is more likely to occur when antibodies induced by a vaccine fail to neutralize the virus because of insufficient concentration, insufficient affinity, or wrong specificity. This phenomenon has typically been described with the dengue viruses and with the cat coronavirus virus, feline infectious peritonitis virus.
On the other hand, VAERD results either from immune complex formation and complement deposition or a T-cell-mediated TH2-biased immune response. The former was observed during a formalin-inactivated whole respiratory syncytial virus (RSV) vaccine trial conducted in the 1960s. Formalin-inactivation RSV resulted in the formation of conformationally incorrect antigens which in turn brought about a high ratio of binding antibody to neutralizing antibody. In the presence of a high viral load, the presence of increased non-neutralizing antibodies leads to the formation of immune complexes and their subsequent deposition, which causes complement activation. Infants who received a formalin-inactivated RSV vaccine and subsequently died after RSV infection demonstrated the previously described findings in their small airways.
Infants that received the formalin-inactivated whole RSV vaccine also exhibited evidence of allergic inflammation in their airways that appeared to be due to a TH2 immune response. These responses are mediated by interleukin (IL) markers IL-4, IL-5, and IL-13 that result in eosinophil recruitment, airway hyperresponsiveness, increased mucus production, and attenuated cytolytic T cell activity.
Prevention of antibody-mediated ADE and VAERD syndromes relies on the use of conformationally correct antigens and host production of neutralizing antibodies. T-cell mediated VAERD can be mitigated with vaccines that favor a TH1 response and CD8+ T cells.
The path to rapid development of safe and effective COVID-19 vaccines for the prevention and mitigation of SARS-CoV-2 infection and disease is challenging. Both traditional and novel vaccine platforms are being thoughtfully incorporated. Throughout the entire process of COVID-19 vaccine development, safety has remained the single most important criterion in their evaluation. Although some COVID-19 vaccine trials include adolescents, vaccine trials in children will most likely await safety and efficacy outcomes from adult trials currently underway.
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