COVID-19 Vaccines

Updated: Apr 14, 2021
  • Author: David J Cennimo, MD, FAAP, FACP, AAHIVS; more...
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Overview

Overview

The genetic sequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was published on January 11, 2020, and the rapid emergence of research and collaboration among scientists and biopharmaceutical manufacturers followed. Various methods are used for vaccine discovery and manufacturing. As of April 6, 2021, The New York Times Coronavirus Vaccine Tracker lists 3 vaccines in emergency use in the United States. Several other vaccines are approved for full use (outside the United States) and 22 vaccines are in phase 3 clinical trials globally. [1]  A number of antiviral medications and immunotherapies are also under investigation for coronavirus disease 2019 (COVID-19). 

The FDA has granted EUAs for 3 SARS-CoV-2 vaccines since December 2020. Two are mRNA vaccines – BNT-162b2 (Pfizer) and mRNA-1273 (Moderna), whereas the third is a viral vector vaccine – Ad26.COV2.S (Johnson & Johnson). Other vaccines are either in or nearing phase 3 trials. 

The Advisory Committee on Immunization Practices published guidelines on ethical principles for the initial allocation of vaccines, [2]  and vaccination efforts are expanding to include more individuals. 

Vaccine Characteristics

In addition to the complexity of finding the most effective vaccine candidates, the production process is also important for manufacturing the vaccine to the scale needed globally. Other variables that increase complexity of distribution include storage requirements (eg, frozen vs refrigerated) and whether more than a single injection is required for optimal immunity. Several technological methods (eg, DNA, RNA, inactivated, viral vector, protein subunit) are available for vaccine development. Vaccine attributes (eg, number of doses, speed of development, scalability) depend on the type of technological method employed. [3, 4, 5]  

Some methods have been used in the development of previous vaccines, whereas others are newly developed. For example, mRNA vaccines for influenza, rabies, and Zika virus have been previously tested in animals. [6]  

Examples of advantages and disadvantages of the various vaccine technologies are included in Table 1. [4, 5, 6]

Table 1. Vaccine Platform Characteristics (Open Table in a new window)

Platform Attributes  Doses Vaccine Candidate (Manufacturer)
mRNA Fast development speed; low- to-medium manufacturing scale 2

BNT-162b2 (Pfizer, BioNTech);

mRNA-1273 (Moderna)

DNA Fast development speed; medium manufacturing scale 2 INO-4800 (Inovio)
Viral vector Medium development; high manufacturing scale 1 or 2

AZD-1222 Ad5-CoV (AstraZeneca; Oxford University);

Ad26.COV2.S (Johnson & Johnson)

Protein subunit Medium- to-fast development; high manufacturing scale  2 NVX-CoV2373 (Novavax)

 

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Vaccines in Late-Stage Development

Three vaccines have gained emergency use authorization (EUA) from the FDA as of April 6, 2021. Others are nearing EUA submission or are in late stage clinical trials. Vaccines available in the United States for EUA include:

  • On February 27, 2021, the US Food and Drug Administration (FDA) granted EUA to Johnson & Johnson for its single dose Ad26.COV2.S vaccine.  
  • On December 18, 2020, the FDA granted EUA for the mRNA-1273 SARS-CoV-2 vaccine in individuals 18 years and older. 
  • On December 11, 2020, the FDA granted EUA for the BNT-162b2 SARS-CoV-2 vaccine in patients 16 years and older.  

BNT-162b2 

Overview

  • EUA in the United States for aged 16 years and older
  • EUA submitted April 9, 2021 for adolescents aged 12-15 years
  • NIH begins phase 2 trial of allergic reactions to vaccine in participants with severe allergies 
  • Phase 3 trials completed in adults and adolescents aged 12 y and older 
  • Phase 2/3 trial in pregnant women started in February 2021 
  • Phase 1/2/3 trials starting spring 2021 in younger children aged 6 months and older 

BNT-152b2 (Pfizer) is a nucleoside-modified messenger RNA (modRNA) vaccine that encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen. It is a 2-dose series given 21 days apart.

A multinational phase 3 trial randomly assigned 43,448 participants to receive vaccine or placebo (vaccine group, 21,720; placebo group, 21,728) by injection. Approximately 42% of global participants and 30% of US participants were of racially and ethnically diverse backgrounds, and 41% of global and 45% of US participants were 56-85 years of age. 

Vaccine efficacy was 95% against the original SARS-CoV-2 strain at 7 days after dose 2, and no serious safety concerns were observed. There were 170 confirmed cases (162 in the placebo group and 8 in the vaccine group); 10 severe cases were reported after the first dose (9 in the placebo group and 1 in the vaccine group). The only grade 3 adverse event with a frequency of greater than 2% was fatigue at 3.8%; headache occurred in 2% of participants. Short-term mild-to-moderate pain at the injection site was the most commonly reported reaction, and severe pain occurred in less than 1% of participants across all age groups. [7]  

Efficacy data in an ongoing, real-world, phase 3 assessment of 46,307 participants showed 91.3% efficacy against COVID-19, when gauged as cases 7 days to 6 months after the second vaccine dose. Among 927 confirmed symptomatic COVID-19 cases, 850 were in the placebo group compared with 77 in the vaccine group. It was 100% effective in preventing severe disease (CDC definition). All 32 severe disease cases were in the placebo group. [8]

Results from an observational study of real world data from healthcare workers (HCWs) employed in a large medical center in Israel after their first vaccine dose have been published. Among 9109 eligible staff, 7214 (79%) had received a first dose and 6037 (66%) had received the second dose between December 19, 2020 and January 24, 2021. Compared with a symptomatic COVID-19 rate of 5 per 10,000 person-days in unvaccinated HCWs, disease rates were 2.8 and 1.2 per 10,000 person-days on days 1-14 and days 15-28 after the first vaccine dose, respectively. Adjusted rate reductions of COVID-19 disease were 47% and 85% for days 1-14 and days 15-28 after the first dose, respectively. [9]  

In another observational study, integrated data repositories in Israel’s largest health care organization were used to evaluate mass immunization effectiveness. The 5 outcomes evaluated included documented SARS-CoV-2 infection, symptomatic Covid-19, hospitalization, severe illness, and death. The observations suggest the vaccine is effective for a wide range of COVID-19–related outcomes that are consistent [10]  with the randomized trial by Polack et al. [7]  

mRNA-1273

Overview

  • EUA in the United States for aged 18 years and older
  • NIH begins phase 2 trial of allergic reactions to vaccine in participants with severe allergies 
  • US phase 3 trial (COVE) completed in adults 
  • Phase 2/3 TeenCOVE trial in adolescents 12-17 y is fully enrolled with approximately 3,000 participants 
  • Phase 2/3 KidCOVE trial children aged 6 months and older began in March 2021 (target enrollment of 6,750) 
  • Phase 2 study started for booster vaccine candidates 
  • Phase 3 trial in university students planned to assess nasal viral load and shedding 

The mRNA-1273 vaccine (Moderna) encodes the S-2P antigen. It is administered as a 2-dose series given 28 days apart. The US phase 3 trial (COVE) launched on July 27, 2020. The trial was conducted in cooperation with the National Institute of Allergy and Infectious Diseases and included more than 30,000 participants who received two 100-mcg doses or matched placebo on days 1 and 29. Results showed an overall efficacy of 94.1% for the original viral strain. There were 196 confirmed cases (185 in placebo group and 11 in vaccine group). Among the 185 cases in the placebo group, 30 cases were severe, including 1 death. [11]  

The COVE study (n = 30,420) included Americans 65 years and older (24.8%), younger individuals with high-risk chronic diseases (16.7%), individuals who identify as Hispanic or Latinx (20.5%), and individuals who identify as Black or African American (10.4%). [11]  Trial data at 6 months after the second dose (ie, as of April 9, 2021) demonstrated efficacy greater than 90% against cases of COVID-19 and greater than 95% against severe cases of COVID-19 in identified cases (data adjudicated from over 900 cases or which over 100 were severe). [12]  

In an ongoing phase 1 trial, 33 adult participants in all age groups showed high antibody activity elicited by mRNA-1273 at 6 months after the second dose. [13]  

Booster vaccine

A preclinical trial conducted by the NIH confirmed improved neutralizing titers with the mRNA-1273.351 vaccine primary series. The multivalent vaccine provided the broadest level of immunity. A boost at 6 months with mRNA-1273.351 closed the neutralizing titer gap for the variants of concern. Following the mRNA-1273.351 boost, neutralizing titers were comparable between the ancestral strain (Wuhan) and the new B.1.351 variant. [14]

Phase 2 trials have started to evaluate COVID-19 booster vaccine candidates. Booster vaccine mRNA-1273.351 encodes for the prefusion stabilized spike protein of the SARS-CoV-2 variant B.1.351, first identified in the Republic of South Africa. mRNA-1273.211 is a multivalent candidate that combines mRNA-1273 ancestral strains and mRNA-1273.351 in a single vaccine. 

Ad26.COV2.S

Overview

  • EUA in the United States for aged 18 years and older
  • Phase 3 trial (ENSEMBLE) completed in adults 
  • Phase 2 trial in pregnant women launched February 2021 
  • Phase 2a trial (ENSEMBLE 2) to assess efficacy of 1 or 2 doses initiated late 2020 
  • ENSEMBLE 2 trial expanded to include adolescents April 2021 

Ad26.COV2.S is an adenovirus serotype 26 (Ad26) recombinant vector-based vaccine (JNJ-78436735, VAC31518; Johnson & Johnson) administered as 1 single injection. 

The phase 3 trial (ENSEMBLE) was launched in September 2020 in the United States, South Africa, and South America. In December 2020, the trial was fully enrolled. Interim results for the phase 1/2a trial describing neutralizing antibody titers of more than 90% at day 29 and 100% at day 57 were published in January 2021. [15]

The EMSEMBLE trial results were released in late January 2021. Safety and efficacy data are based on 43,783 participants randomized 1:1 accruing 468 symptomatic cases of COVID-19. FDA analysis of the data at Day 28 determined the vaccine was 72% effective in the Unites States, 61% in Latin America, and 64% in South Africa (where the B.1.351 variant was circulating) at preventing moderate-to-severe COVID-19 infection. Importantly, the vaccine was 85% effective in preventing severe disease in all geographic regions. Efficacy against severe disease increased over time with no cases in vaccinated participants reported after day 49. Additionally, the vaccine provided 100% protection against COVID-19 related hospitalization and death at Day 28. [16]  

Additionally, Ad26.COV2.S showed consistent protection across race, age groups, including older adults (participants aged 60 years and older were 34.6% of the vaccine arm), and across all variants and regions studied, including South Africa where nearly all cases of COVID-19 (95%) were due to infection with a SARS-CoV-2 variant from the B.1.351 lineage. [16]  

The EUA Fact Sheet for Health Care Professionals states efficacy of the vaccine in older study participants showed no overall differences in safety or efficacy compared with younger participants. At least 28 days post vaccination, efficacy against moderate to severe/critical disease at all study sites (ie, United States, Latin America, South Africa) was 66.2% for those aged 60 years and older compared with 66.1% for those aged 18-59 years. In the United States, estimated efficacy was 85.9% at least 28 days after vaccination. 

NVX-CoV2373 

Overview

  • Preliminary results published from phase 3 trial in the United Kingdom 
  • Preliminary results published from phase 2b in South African 
  • Phase 3 trial (PREVENT-19) in United States and Mexico; approximate enrollment of 30,000 completed mid-February 2021 
  • Crossover studies initiated in ongoing trials in South Africa, the United Kingdom, and the United States in March/April 2021 to ensure all participants receive vaccine

NVX-CoV2373 (Novavax) is engineered using recombinant nanoparticle technology from SARS-CoV-2 genetic sequence to generate full-length, prefusion spike (S) protein. This is combined with an adjuvant (Matrix-M). Results of preclinical studies showed that it binds efficiently with human receptors targeted by the virus. It is administered as a 2-dose series given 21 days apart. 

Phase 1/2 trials were initiated in May 2020. Phase 1 data in healthy adults showed that the adjuvanted vaccine induced neutralization titers that exceeded responses in convalescent serum from mostly symptomatic patients with COVID-19. [17]   

The phase 3 trial in the United Kingdom has completed enrollment and the phase 2b trial in South Africa has reported final results. [18]  Results of these trials are timely, as new circulating viral variants in The United Kingdom and South Africa have emerged during the trials. 

UK phase 3 results [18]

The study enrolled more than 15,000 adults aged 18-84 years, including 27% older than 65 years. 

  • Final analysis based on 106 cases (96 placebo, 10 in NVX-CoV2373) 
  • 101 cases were mild or moderate; 5 were severe (placebo group); 4 of the 5 attributed to B.1.1.7 variant (UK strain)
  • Calculated efficacy UK strain: 86.3%
  • Calculated efficacy original strain: 96.4%

South Africa phase 2b results [18]

This study enrolled over 4,400 patients beginning in August 2020, with COVID-19 cases counted from September through mid-January. During this time, the triple mutant variant, containing 3 critical mutations in the RBD and multiple mutations outside the RBD, was widely circulating in South Africa.

  • 55.4% efficacy for the prevention of mild, moderate, and severe COVID-19 disease was observed in the study population that was HIV-negative (N = 2,665)
  • 48.6% overall efficacy with results from both patient populations (ie, HIV positive and negative) 
  • 100% protection against severe disease, including all hospitalization and death

AZD-1222

Overview

  • Pending EUA submission in the United States; approved for use in United Kingdom and other countries 
  • Phase 3 trials in United States completed March 2021 
  • Phase 3 trial in United Kingdom planned to assess safety and immune response in children and young adults aged 6-17 years 

AZD-1222 (ChAdOx1 nCoV-19; AstraZeneca) is a replication-deficient chimpanzee adenoviral vector vaccine containing the surface glycoprotein antigen (spike protein) gene. It is administered as a 2-dose series 28 days apart. This vaccine primes the immune system by eliciting antibodies to attack the SARS-CoV-2 virus if it later infects the body. Owing to the testing of a different coronavirus vaccine in 2019, development for AZD-1222 was faster than that of other viral vector vaccines.

Results of an interim analysis of the phase 3 clinical trial in the United Kingdom, Brazil, and South Africa are as follows:

One dosing regimen (n = 2741) showed vaccine efficacy of 90% when given as a half dose, followed by a full dose at least 1 month later. Another dosing regimen (n = 8895) showed 62.1% efficacy when given as 2 full doses at least 1 month apart. The combined analysis from both dosing regimens (N = 11,636) resulted in an average efficacy of 70.4% ( < .0001 for all). From 21 days after the first dose, 10 patients in the control arm were hospitalized for COVID-19 (2 severe, 1 death). [19]  Concerns about the clinical trial implementation and data analysis have emerged because the half-dose regimen was not in the approved study design. [20]  These concerns will be addressed by regulatory agencies and await publication of the trial data. 

In another trial, researchers studied the second vaccine dose administered at 3 months after the first dose instead of at 1 month. There were no hospitalizations in the vaccine group after the initial 21-day exclusion period compared with 15 in the control group. Vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 was 76%. Modelled analysis indicated that protection did not wane during the initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90. In the group that received 2 doses of the standard dose, vaccine efficacy was higher with a longer prime-boost interval (3 months) compared with an interval less than 6 weeks (82.4% vs 54.9% respectively). [21]

Additionally, nasal swabs were obtained from trial participants every week in the UK study, regardless of symptoms. This allowed assessment of the overall impact of the vaccine on risk of infection, and thus a surrogate for potential onward transmission. A single standard dose of AZD-1222 reduced PCR positivity by 67%, and after the second dose, reduced PCR positivity by 49.5% overall. These data indicate that ChAdOx1 nCoV-19, used in the authorized schedules, may have a substantial impact on transmission by reducing the number of infected individuals in the population. [21]

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Viral Variants and Vaccines

Mutations

Viral mutations may naturally occur anywhere in the SARS-CoV-2 genome. Unlike the human DNA genome, which is slow to mutate, RNA viruses are able to readily, and quickly, mutate. A mutation may alter the viral function (eg, enhance receptor binding), or may have no discernable function. A new virus variant emerges when the virus develops 1 or more mutations that differentiate it from the predominant virus variants circulating in a population. The CDC surveillance of SARS-CoV-2 variants includes US COVID-19 cases caused by variants. The site also includes which mutations are associated with particular variants. The CDC has launched a genomic surveillance dashboard and a website tracking US COVID-19 case trends caused by variants. Researchers are studying how variants may or may not alter the extent of protection by available vaccines. 

Variants of concern

Variants of concern (VOCs) may reduce vaccine effectiveness, which may be evident by a high number of vaccine breakthrough cases or a very low vaccine-induced protection against severe disease. The CDC tracks variant proportions in United States and estimated the B.1.1.7 variant (first detected in the United Kingdom) accounted for over 27% of cases from January 2 to March 13, 2021. On April 7, 2021, the CDC announced B.1.1.7 is the dominant strain circulating in the United States.  

Enhanced genomic surveillance in some countries has detected other VOCs. These include B.1.351 (501Y.V2) first detected in South Africa and the B.1.1.28 (renamed P.1) (501Y.V3), which was detected in 4 travelers from Brazil during routine screening at the Tokyo airport. [22]  A change of the B.1.1.7 variant that includes the E484K mutation (B.1.1.7+E484K) was discovered in early 2021 that furthers these concerns. The CDC is also tracking VOCs B.1.427 and B.1.429, which emerged in California. 

The immune response provoked by vaccines includes protection from the antigen by eliciting antibodies, T-cells, and interferons. Variants that have emerged in the United Kingdom and South Africa in late 2020 have multiple mutations in their S glycoproteins (ie, the spike protein), which are key targets of currently available vaccines. [23]  

BNT162b2 vaccine

A two-thirds reduced neutralization of BNT162b2 vaccines against the B.1.351 variant was shown in vitro when compared with the reference viral strain. [24]  

Other in vitro studies comparing sera of neutralizing antibody titers from participants in vaccine studies described use of sera from BNT162b2 SARS-CoV-2 vaccine showed no reduction in neutralization of pseudoviruses bearing the B.1.1.7 variant (ie, UK variant) [23, 25]  and the B.1.351 variant (ie, South African variant). [23]  

However, another study suggests that antibodies elicited by primary infection and by the BNT162b2 mRNA vaccine are likely to maintain protective efficacy against B.1.1.7 and most other variants, but that the partial resistance of virus with the B.1.351 spike protein could render some individuals less well protected, supporting a rationale for the development of modified vaccines containing the E484K mutation. [26]

mRNA-1273 vaccine

Similarly, the mRNA-1273 vaccine neutralizing capabilities were assessed against the UK and South African variants. No significant impact on neutralization against the B.1.1.7 variant was detected in the first phase of testing and reported in February 2021. In contrast, just a month later, decreased titers of neutralizing antibodies were observed against the P.1 variant, the B.1.427/B.1.429 variant (versions 1 and 2), the B.1.1.7+E484K variant, and the B.1.351 variant as well as a subset of its mutations in the RBD. The researchers detected reductions by a factor of between 2.3 and 6.4 in titers of neutralizing antibodies against the tested panel of variants. The largest effect on neutralization, reduction by a factor of 6.4, was measured against the B.1.351 variant. [27]   

A slight decreased neutralization is not considered to be clinically significant regarding vaccine efficacy, owing to the very high efficacy of each mRNA vaccine (ie, approximately 95%) to the Wuhan reference viral strain. Continued variant surveillance in both nonhuman primates and humans will allow foresight for any needed changes to vaccine development or future booster doses that may be warranted. In February, 2021, Moderna announced it is advancing its variant-specific vaccine candidate, mRNA-1273.351, against the B.1.351 variant first identified in South Africa into preclinical studies and a Phase 1 study in the United States. A multivalent booster candidate, mRNA-1273.211, which combines mRNA-1273 and mRNA-1273.351 in a single vaccine and a third lower-dose of mRNA-1273 vaccine have also been forwarded to the National Institutes of Health for phase 1 clinical testing. 

NVX-CoV2373 vaccine

Novavax confirmed preliminary efficacy results for NVX-CoV2373 vaccine from the phase 3 trial in the United Kingdom (n > 15,000). The final analysis showed vaccine efficacy of 96.4% against the original strain of SARS-CoV-2. [18]  

Final analysis from the Phase 2b trial (n > 4,400) conducted in South Africa for NVX-CoV2373 reported 55.4% efficacy among HIV-negative participants. The South African escape variant was the predominant variant (more than 90% of cases analyzed). [18]  

Ad26.COV2.S vaccine

Johnson & Johnson reported phase 3 trial results (EMSEMBLE; n= 43,783) for their single-dose Ad26.COV2.S viral vector vaccine in late January 2021. The trial was conducted in geographical regions and during the time when several variants emerged.  FDA analysis of the data at Day 28 determined the vaccine was 72% effective in the United States, 61% in Latin America, and 64% in South Africa at preventing moderate-to-severe COVID-19 infection. Importantly, the vaccine was 85% effective in preventing severe disease and provided complete protection against COVID-related hospitalization and death in all geographic regions. Additionally, it showed consistent protection across all variants and regions studied, including South Africa where nearly all cases of COVID-19 (95%) were due to infection with a SARS-CoV-2 variant from the B.1.351 lineage. [16]  

AZD-1222 (ChAdOx1 nCoV-19) vaccine

A study in the United Kingdom between October 1, 2020 and January 14, 2021 determine efficacy of AZD-1222 against the B.1.1.7 variant is similar to the efficacy of the vaccine against other lineages. [28]   

Minimal protection against mild-to-moderate COVID-19 infection from the B.1.351 variant in South Africa was observed following 2 doses in non-HIV infected young adults (n ~2000). Mild-to-moderate COVID-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9%. Among the 42 participants with COVID-19, 39 cases (92.9%) were caused by the B.1.351 variant. The incidence of serious adverse events was balanced between the vaccine and placebo groups. These results prompted South Africa to halt roll out of the vaccine in early February. [29]

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Other Investigational Vaccines

Additional vaccine candidates are in various stages of development and clinical testing. Examples of these vaccines are provided in Table 2.

Table 2. Other Investigational Vaccines (Open Table in a new window)

Vaccine Comments

INO-4800 (Inovio Pharmaceuticals) [30]

 

DNA-based, 2-dose vaccine 

Stable at room temperature for more than 1 y; frozen shipment not needed; interim results from phase 1 human trial (n = 40): favorable safety and immunogenicity; expanded to include older participants. [31]

Phase 2/3 trial (INNOVATE) ongoing; phase 2 to evaluate 2-dose regimen (1 mg or 2 mg) vs placebo in 400 participants.

Grant from Bill and Melinda Gates Foundation to speed testing and scale up a smart device (Cellectra 3PSP) for large-scale intradermal vaccine delivery; company has also received funds from the US Department of Defense.

CVnCoV (CureVac) [32]

 

mRNA, 2-dose vaccine

Phase 2b/3 trial (HERALD) was initiated in December 2020 of mRNA 12-mcg dose (2 doses on days 1 and 29) in multiple European and Latin American sites with goal of 35,000 participants enrolled. Partnering with Bayer, GlaxoSmithKline, and Novartis for production.  
Recombinant protein adjuvanted vaccine (Sanofi and GSK) [33] Randomized, double-blind, multi-center dose finding study conducted in adults aged 18 years of age and older to evaluate the safety, reactogenicity, and immunogenicity of 2 injections given 21 days apart. The trial will include equal numbers of adults aged 18-59 years and those aged 60 years and older. Study initiated Q1 2021 plans to refine antigen formulation to achieve optimal immune response in older adults.Previous phase 1/2 study showed lower immune response in adults, likely owing to insufficient concentration of antigen.
CpG 1018 adjuvanted vaccine (Clover and Dynavax) [34]   Phase 2/3 trial of Clover’s protein-based S-Trimer COVID-19 subunit vaccine adjuvanted with Dynavax’s CpG 1018 plus alum planned for early 2021. 
UB-612 multitope peptide-based vaccine (COVAXX [United Biomedical, Inc]) [35]  

Comprised of SARS-CoV-2 amino acid sequences of the receptor binding domain; further formulated with designer Th and CTL epitope peptides derived from the S2 subunit, membrane, and nucleoprotein regions of SARS-CoV-2 structural proteins for induction of memory recall, T-cell activation, and effector functions against SARS-CoV-2. Starting phase 2 trial in Taiwan and phase 2/3 trial in Brazil in Q1 2021. Covaxx is merging with its sister company (United Neuroscience) to form a new company call Vaxinity to include both companies’ vaccine platforms. 

HaloVax (Hoth Therapeutics; Voltron Therapeutics) [36]   Collaboration with the Vaccine and Immunotherapy Center at Massachusetts General Hospital; use of VaxCelerate self-assembling vaccine platform offers 1 fixed immune adjuvant and 1 variable immune target to allow rapid development.
Nanoparticle SARS-CoV-2 vaccine (Ufovax) [37]   Vaccine prototype development utilizing self-assembling protein nanoparticle (1c-SapNP) vaccine platform technology.
PDA0203 (PDS Biotechnology Corp) [38]   Utilizes Versamune T-cell-activating platform for vaccine development.
CoVLP (Medicago and GlaxoSmithKline) [39]   Combines Medicago’s recombinant coronavirus virus-like particles (rCoVLP) with GSK’s adjuvant system. Phase 3 trial initiated in March 2021 with goal of enrolling 30,000 participants initially in healthy adults aged 18-65 y, followed by individuals aged 65 y and older with comorbidities. The trial will take place in 10 countries, initially starting in Canada and the US. 

Covaxin (BBV152; Bharat Biotech and Ocugen) [40]  

Whole-virion inactivated COVID-19 vaccine candidate. Developed and manufactured in Bharat Biotech’s bio-safety level 3 biocontainment facility. Co-development with Ocugen announced for the US market. Received EUA in India in January 2021 following a fully enrolled phase 3 trial (n ~25,800). Interim phase 3 results in India reported 81% efficacy.

Recombinant adenovirus type-5-vectored vaccine (Ad5-vectored vaccine; Sinopharm [China]) [41]   Approved in China and Saudi Arabia; preliminary data: 86% efficacy; phase 2 trial: seroconversion of neutralizing antibodies seen in 59% and 47% of those in 2-dose groups; seroconversion of binding antibody seen in 96-97% of participants; Positive specific T-cell responses seen in 88-90% of participants. 
CoronaVac (Ad5-vectored vaccine; Sinovac [China]) [42]   Limited use in China. Interim phase 3 efficacy reports vary widely from several trials. A trial in Brazil reports efficacy of 50-90%. However, a Turkish trial reports 91.25% efficacy (n = 7,371; data analysis based on 1322 participants – 752 vaccine and 570 placebo).
rAd26 (frozen) and rAd5 vector-based (lyophilized) formulations (Sputnik V; Moscow Gamaleya Institute) [43] Approved in Russia. Each vaccine vector carries gene for full-length SARS-CoV-2 glycoprotein S. The phase 3 trial administered 2 doses 21 days apart (rAd26 then rAd5) assigned in a 3:1 ratio of vaccine (n = 16,501) or placebo (n = 5,476). Interim analysis of results 21-days after the first dose (ie, day of dose 2) showed confirm COVID-19 infection in 0.1% of the vaccine group compared with 1.3% of the placebo group translating to 91.3% efficacy. 
hAd5 T-cell (ImmunityBio and NantKwest) [44]  

Phase 1 trial ongoing; vaccine targets inner nucleocapsid (N) and outer spike (S) protein, which have been engineered to activate T cells and antibodies against SARS-CoV-2, respectively.

These dual constructs offer the possibility for the vaccine candidate to provide durable, long-term cell-mediated immunity with potent antibody stimulation to patients against both the S and N proteins.

Phase 1 trial expanded to include the initial SC prime vaccine with a room-temperature oral or sublingual booster to induce comprehensive immune protection and generate both systemic and mucosal antibodies. 

MRT5500 (Sanofi and Translate Bio) [45] mRNA-based vaccine candidate; preclinical evaluation demonstrated favorable ability to elicit neutralizing antibodies using a 2-dose schedule administered 3 wk apart in Fall 2020. Despite this, Sanofi announced the vaccine will not be ready to start clinical trials until second half of 2021 and it could be of use at a later stage against variants. 
AG0302-COVID19 (AnGes and Brickell Biotech) [46]   Adjuvanted DNA vaccine in phase 1/2 study in Japan; data readouts expected in Q1 2021; intent to follow with phase 3 trials in United States and South America. 
SARS-CoV-2 spike ferritin nanoparticle (spFN) vaccine with ALFQ adjuvant (Walter Reed Army Institute of Research) [47]   Phase 1 study launched April 1, 2021. Preclinical trial in monkeys showed 2-dose vaccine delivered high antibody levels. Development plans include new vaccine version with proteins from other coronaviruses. 
EPV-CoV-19 (EpiVax)  Subunit, T-cell epitope-directed vaccine. Preclinical validation studies completed. Clinical trial anticipated in early 2021. 

Discontinued vaccine development

 

Vaccine candidates V590 and V591 (Merck) [48]

V590 and V591 (subunit vaccines): Phase 1 studies showed immune responses were inferior to natural infection and those reported for other SARS-CoV-2 vaccines. 

 

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Noninjectable Investigational Vaccines

Routes of vaccine administration other than injection are also undergoing development.

Table 3. Noninjectable Investigational Vaccines (Open Table in a new window)

Noninjectable Vaccine Comments
hAd5 T-cell  (ImmunityBio and NantKwest) [44]  

Vaccine targets inner nucleocapsid (N) and outer spike (S) protein, which have been engineered to activate T cells and antibodies against SARS-CoV-2, respectively. 

Phase 1 trial expanded to include the initial SC prime vaccine with a room-temperature oral or sublingual booster to induce comprehensive immune protection and generate both systemic and mucosal antibodies. 

Intranasal COVID-19 vaccine (AdCOVID; Altimmune, Inc) [49]   Phase 1 dose-ranging study of 1 or 2 intranasal doses initiated in February 2021. The trial will evaluate safety and immunogenicity in up to 180 participants aged 18-55 years.  
ChAdOx1 nCov-19 inhaled (University of Oxford) [50]   Dose-ranging trial for orally inhaled vaccine beginning phase 1 trials in 30 volunteers in Fall 2020. 
saRNA inhaled (Imperial College of London) [50]   Dose-ranging trial for orally inhaled vaccine beginning phase 1 trials in 30 volunteers in Fall 2020. 
VXA-CoV2-1 oral vaccine (Vaxart) [51]   Recombinant adenovirus vector type 5 (Ad5) expressing coronavirus antigen and a toll-like receptor 3 (TLR3) agonist as an adjuvant. Preliminary phase 1 trial (n = 495) showed induced CD8 T-cell responses to the viral spike protein. Neutralizing antibodies not detected in most subjects. Company is evaluating optimal dosing schedule in order to assess efficacy in phase 2 trials. 
PittCoVacc (University of Pittsburgh School of Medicine) [52]   Vaccine candidate using transdermal microneedle for COVID-19; testing in mice produced antibodies over a 2-wk period; microneedles are made of sugar, making it easy to mass-produce and store without refrigeration.
MV-014-212 (Meissa Vaccines) [53]   Intranasal live attenuated vaccine. Generates both mucosal IgA antibodies in nasal cavity and systemically circulating antibodies. The company created the SARS-CoV-2 intranasal vaccine using their existing RSV vaccine platform. Phase 1 dose-escalating study announced in March 2021. 

 

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COVID-19 Vaccination While Pregnant or Lactating

Data from the Centers for Disease Control and Prevention (CDC) states that pregnant women are at an increased risk for severe illness from coronavirus disease 2019 (COVID-19) and death, compared with nonpregnant individuals. In addition, pregnant women may be at increased risk for other adverse outcomes (eg, preterm delivery). The CDC has issued Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines, which discusses the limited data available regarding administration to pregnant women. Owing to these risks, preventing severe COVID-19 infection is essential for both mother and fetus. 

A cohort study (n = 131) by Gray et al found mRNA SARS-CoV-2 vaccines generated humoral immunity in pregnant and lactating women, similarly to that observed in nonpregnant women. All serum titers from vaccination were significantly higher compared with titers induced by SARS-CoV-2 infection during pregnancy (p < 0.0001). Importantly, vaccine-generated antibodies were present in all umbilical cord blood and breastmilk samples, showing immune transfer to neonates vial placenta and breastmilk. [54]  In another study, maternal and cord blood sera were collected from 20 parturients who received 2 doses of the mRNA BNT162b2 vaccine. All women and infants were positive for anti S- and Anti-RBD-specific IgG. [55]  

Additional studies support the above findings in cord blood and provide further information regarding potential timing of maternal vaccination. In one study (n = 27), mean placental IgG transfer ratio following vaccination (mRNA vaccines) provides about an equal in infant antibody level to maternal level. It also appears to increase with latency from vaccination, suggesting that earlier vaccination in the third trimester may produce greater infant immunity. [56]  A similar study (n = 122) observed women vaccinated with mRNA vaccines lead to maternal antibody production as soon as 5 days after the first dose and passive immunity to the neonate as soon as 16 days. The placental IgG transfer ratio increased over time. [57]  

The American College of Obstetricians and Gynecologists (ACOG) has issued guidelines regarding vaccination of pregnant and lactating patients against COVID-19. Key points from these guidelines are as follows: 

  • Do not withhold COVID-19 vaccines from pregnant women. 
  • Although a conversation with a clinician may be helpful, it should not be required before vaccination, since this may cause unnecessary barriers to access. 
  • COVID-19 vaccines should be offered to lactating individuals on the same basis as they are offered to nonlactating individuals.

Individuals considering COVID-19 vaccination should have access to information about vaccine safety and efficacy, including information about data that are not available. A conversation between the patient and the clinical team providing care may assist with decisions regarding the use of vaccines approved by the FDA under emergency use authorization for the prevention of COVID-19 in pregnant patients. Important considerations include:

  • Level of viral activity in the community
  • Potential efficacy of the vaccine
  • Risk and potential severity of maternal disease, including the effects of disease on the fetus and newborn
  • Safety of the vaccine for the pregnant patient and fetus

Phase 2/3 clinical trials in pregnant women commenced in February 2021 with the BNT162b2 vaccine and the Ad26.COV2.S vaccine is planned for spring 2021.

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