COVID-19 Vaccines

Updated: Jun 16, 2021
  • Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; more...
  • Print
Overview

Overview

After publication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic sequence on January 11, 2020, research and collaboration among scientists and biopharmaceutical manufacturers quickly followed.

Various methods are used for vaccine discovery and manufacturing. As of May 5, 2021, The New York Times Coronavirus Vaccine Tracker lists 3 vaccines authorized for emergency use in the United States. Several other vaccines are approved for full use outside the United States, and 27 vaccines are in phase 3 clinical trials globally. [1]  Numerous antiviral medications and immunotherapies are under investigation for coronavirus disease 2019 (COVID-19). 

The US Food and Drug Administration (FDA) has granted emergency use authorizations (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 in or nearing phase 3 trials. 

Vaccination of older adults in nursing homes began in January 2021 and has already profoundly reduced severe outcomes and hospitalizations in patients at higher risk, including older adults. [2]  

Vaccination in previously infected individuals

The CDC recommends vaccination for individuals who have already had COVID-19 and recovered. Vaccinations provide a safer and more reliable way to build antibodies compared with infection. Patients may receive the vaccine once they have recovered from the acute illness (if symptomatic) and meet the criteria to discontinue isolation. Patients who received monoclonal antibodies or convalescent plasma should wait 90 days before receiving the vaccine.

Evidence shows vaccines provide substantially higher protection against COVID-19 infection compared with immunity from a previous COVID-19 infection. mRNA vaccinees have higher antibody titers (up to 10 times higher) than convalescent plasmas from donors who recovered from natural infection. [3]  

Early studies found vaccination of patients with prior SARS-CoV-2 infection enhances T-cell immunity and antibody-secreting memory B-cell response, and neutralizing antibodies effective against emerging variants. These data emphasize the importance of vaccinating both uninfected and previously infected persons to elicit cross-variant neutralizing antibodies. [4, 5, 6]  

Vaccination in adolescents and children

In the United States, vaccination was opened to all aged 16 years and older in early April 2021. On May 10, 2021, the FDA extended the EUA for the BNT162b2 vaccine (Pfizer) to include younger adolescents aged 12-15 years. The phase 3 trial data that is included in the EUA lists the vaccine as 100% effective in preventing SARS-CoV-2 infection in this age group. There were no cases of COVID-19 disease in adolescents aged 12-15 years who received the vaccine (n = 1,119) compared with 18 cases in those who received placebo (n = 1,110). 

The mRNA-1273 vaccine (Moderna) was reported to be 100% effective 14 days after receiving 2 doses  in adolescents aged 12-17 years. In addition, vaccine efficacy of 93% in seronegative participants was observed starting 14 days after the first dose using the secondary CDC case definition of COVID-19, which tested for milder disease. The phase 2/3 trial included 3,732 participants. An EUA was submitted June 10, 2021 to expanded the current EUA to include this population. 

A trial for NVX-CoV2373 (Novavax) in adolescents aged 12-17 years has enrolled 2,248 participants as of mid-June 2021. 

Clinical trials for other vaccines are ongoing for adolescents and children.

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. [7, 8, 9]  

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. [10]  

Examples of advantages and disadvantages of the various vaccine technologies are included in Table 1. [8, 9, 10]

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)
Whole virion inactivated 

Ability to quickly produce large amounts of vaccine

2

Covaxin; BBV152 (Ocugen and Bharat Biotech)

 

Next:

mRNA Vaccines

BNT-162b2 

Overview

  • Rolling BLA submitted May 7, 2021 to FDA for full approval for individuals aged 16 years and older
  • EUA granted in the United States for individuals aged 12 years and older 
  • NIH  phase 2 trial of allergic reactions to vaccine in participants with severe allergies underway
  • Phase 3 trials complete in adults and adolescents aged 12 years and older 
  • Phase 2/3 trial in pregnant women started in February 2021 
  • Phase 1/2/3 trials starting spring 2021 in infants and younger children aged 6 months and older 
  • Phase 3 trial in older adults of BNT-162b2 booster dose followed by 20-valent pneumococcal conjugate vaccine (20vPnC) 

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 (placebo group, 162; vaccine group, 8); 10 severe cases occurred after the first dose (placebo group, 9; vaccine group, 1). 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 common reaction, and severe pain occurred in less than 1% of participants across all age groups. [11]  

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 (Centers for Disease Control and Prevention [CDC] definition). All 32 severe disease cases occurred in the placebo group. [12]

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%) received a first dose and 6037 (66%) received the second dose in December 2020 and January 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% for days 1-14 and 85% for days 15-28 after the first dose. [13]  

In another observational study, researchers used integrated data repositories in Israel’s largest health care organization to evaluate mass immunization effectiveness. The 5 outcomes evaluated were 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 [14]  with the randomized trial by Polack et al. [11]  

mRNA-1273

Overview

  • EUA in the United States for adults aged 18 years and older 
  • EUA submitted June 10, 2021 for adolescents based on phase 2/3 TeenCOVE trial (n = 3,732) completed in adolescents aged 12-17 years showing 100% efficacy after 2 doses
  • June 1, 2021: Rolling BLA initiated for U.S. licensure in adults
  • NIH  phase 2 trial of allergic reactions to vaccine in participants with severe allergies underway
  • US phase 3 trial (COVE) in adults complete  
  • Phase 2/3 KidCOVE trial children aged 6 months and older began in March 2021 (target enrollment 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 in July 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. Overall efficacy was 94.1% for the original viral strain. There were 196 confirmed cases (placebo group, 185; vaccine group, 11). Among the 185 cases in the placebo group, 30 cases were severe, including 1 death. [15]  

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%). [15]  At 6 months after the second dose, efficacy was greater than 90% against COVID-19 infection and greater than 95% against severe COVID-19 in identified cases (data adjudicated from over 900 cases, of which over 100 were severe). [16]  

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. [17]  

Booster vaccine

A single booster dose of mRNA-1273 or mRNA-1273.351 increased neutralizing titers against SARS-CoV-2 and 2 variants of concern (B.1.351, P.1) in previously vaccinated clinical trial participants. A booster dose of mRNA-1273.351, a strain-matched candidate, achieved higher titers against B.1.351 than a booster dose of mRNA-1273. [18]

Evaluation of a multivalent vaccine booster, mRNA-1273.211, that combines mRNA-1273 ancestral strains and mRNA-1273.351 in a single vaccine is ongoing. 

Previous
Next:

Viral Vector Vaccines

Ad26.COV2.S

Overview

  • EUA in the United States for adults aged 18 years and older
  • Phase 3 trial (ENSEMBLE) in adults completed  
  • Phase 2 trial in pregnant women launched February 2021 
  • Phase 2a trial (ENSEMBLE 2) to assess efficacy of 1 or 2 doses began 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) began in September 2020 in the United States, South Africa, and South America. In December 2020, it 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. [19]

The EMSEMBLE trial randomly assigned more than 40,000 participants worldwide to receive 1 injection of either Ad26.COV2.S (n = 19,630) or placebo (n = 19,691). Ad26.COV2.S protected against moderate to severe–critical Covid-19 with onset at least 14 days after administration (vaccine group,116 cases; placebo group, 348; efficacy, 66.9%) and at least 28 days after administration (66 vs 193 cases; efficacy, 66.1%). The vaccine showed higher efficacy against severe–critical Covid-19 (76.7% for onset at 14 days and 85.4% for onset at 28 days). The vaccine was 100% effective against COVID-19–related hospitalization and death at Day 28; 16 hospitalizations occurred in the placebo group. [20]  

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. [20]  

The EUA Fact Sheet for Health Care Professionals states the vaccine's safety and efficacy in older study participants showed no overall differences 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 18-59 years. In the United States, estimated efficacy was 85.9% at least 28 days after vaccination.  

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). [21]  Concerns about the clinical trial implementation and data analysis have emerged because the half-dose regimen was not in the approved study design. [22]  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. After the initial 21-day exclusion period, there were no hospitalizations in the vaccine group 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). [23]

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 for 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. [23]  

Thrombosis with thrombocytopenia syndrome (TTS) 

Cases of thrombosis with thrombocytopenia with the Ad26.COV2.S (Janssen [Johnson & Johnson]) and AZD-1222 (ChAdOx1 nCoV-19; AstraZeneca) vaccines have been reported. The FDA temporarily paused use of Ad26.COV2.S in mid-April 2021 to allow the CDC's Advisory Committee on Immunization Practices (ACIP) to evaluate rare cases of cerebral venous sinus thrombosis. After discussing the benefits and risks of resuming vaccination, ACIP reaffirmed its interim recommendation for use of the Janssen COVID-19 vaccine in all persons aged 18 years and older under the FDA’s EUA. The EUA now includes a warning that rare clotting events may occur after vaccination, primarily among women aged 18-49 years. The risk for death and serious outcomes of COVID-19, including thrombosis, far outweigh the risk for TTS possibly associated with highly efficacious vaccines. [24]   

TTS is a rare syndrome that involves acute venous or arterial thrombosis and new-onset thrombocytopenia in patients with no known recent exposure to heparin. Although the mechanism that causes TTS is not fully understood, and appears similar to heparin-induced thrombocytopenia, a rare reaction to heparin treatment. In the United States, 12 of 15 persons with TTS that occurred after Janssen COVID-19 vaccination had CVST with thrombocytopenia. [24]   

The American Society of Hematology and the American Heart Association/American Stroke Association have published documents for clinicians to be aware of symptoms, diagnosis, and urgent treatment if TTS is suspected.  

Diagnosis includes the following 4 criteria:

  • COVID vaccine (Johnson & Johnson/AstraZeneca only to date) 4 to 30 days previously  
  • Venous or arterial thrombosis (often cerebral or abdominal) 
  • Thrombocytopenia 
  • Positive PF4 ‘HIT’ (heparin-induced thrombocytopenia) ELISA 

The following symptoms associated with TTS may emerge 4-30 days after vaccination with Ad26.COV2.S or AZD-1222:

  • Severe headache 
  • Visual changes Abdominal pain 
  • Nausea and vomiting 
  • Back pain 
  • Shortness of breath 
  • Leg pain or swelling 
  • Petechiae, easy bruising, or bleeding 
Previous
Next:

Protein Subunit Vaccines

NVX-CoV2373 

Overview

  • Phase 3 trial (PREVENT-19) demonstrated 90.4% overall efficacy and 100% protection against moderate-to-severe disease 
  • 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
  • Trial in adolescents aged 12-17 years has enrolled 2,248 participants as of mid-June 2021 with enrollment goal of 3,000 across 75 US sites 
  • Refrigerate (2-8ºC) for shipping and storage; solution for IM injection 

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. 

The PREVENT-19 phase 3 clinical trial demonstrated overall efficacy of 90.4%. Results are based on 77 cases of symptomatic COVID-19 that investigators observed among trial participants from January 25 through April 30, 2021. There were 63 cases among the approximately 10,000 participants who received placebo and 14 cases among the approximately 20,000 participants who received the investigational vaccine. Of the 63 COVID-19 cases in the placebo group, investigators classified 10 as moderate and 4 as severe. There were no cases of moderate or severe disease in the investigational vaccine group. [25]   

The phase 3 trial in the United Kingdom has completed enrollment and the phase 2b trial in South Africa has reported final results. [26]  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  [26]

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  [27]

Among over 6000 participants who underwent screening, 4,387 patients received at least 1 injection of vaccine or placebo 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.

  • 60.1% efficacy for the prevention of mild, moderate, and severe COVID-19 disease was observed in the study population that was baseline seronegative and HIV-negative
  • 49.4% overall efficacy with results from both patient populations (ie, HIV positive and negative) 
  • 100% protection against severe disease observed, including all hospitalization and death
Previous
Next:

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. In mid-June 2021, it remains the dominant strain accounting for approximately 70% of new cases. 

On June 15, 2021, the CDC named the Delta variant (B.1.617.2) that originated in India a variant of concern in the United States. As of mid-June 2021, the CDC estimates the Delta variant accounts for 10% of new cases 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. [28]  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. [29]  

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. [30]  

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) [29, 31]  and the B.1.351 variant (ie, South African variant). [29]  

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. [32]  

The Delta variant (B.1.617.2) has rapidly spread in India is emerging in the United States mid-2021. It became the predominant variant in the United Kingdom during Spring 2021. Edra et al found this variant 6.8-fold more resistant to neutralization by sera from COVID-19 convalescent and mRNA vaccinated individuals. [33]  However, a study completed by Public Health England found the BNT162b2 vaccine was slightly reduced from 93.4% with the B.1.1.7 variant to 87.9% for the Delta variant 2 weeks after the second dose. [34]   Another U.K. analysis found single-dose recipients neutralizing antibodies are significantly lower against B.1.617.2 and B.1.351 VOCs relative to B.1.1.7, implying that although a single dose might still afford considerably more protection than no vaccination, single-dose recipients are likely to be less protected against these SARS-CoV-2 variants. [35]  These data stress the importance of receiving 2 doses and adhering to the typical regimen of injections approximately 3 weeks apart. 

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. [36]   

Edra et al estimated the Delta variant (B.1.617.2), first identified in India, to be 6.8-fold more resistant to neutralization by sera from COVID-19 convalescent and mRNA vaccinated individuals. [33]  

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. [26]  

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). [26]  

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. [20]  

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. [37]   

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. [38]  

A study completed by Public Health England found 2 dose effectiveness reduced from 66.1% for the B.1.1.7 variant to 59.8% for the B.1.617.2 variant (Delta) first identified in India, which is the dominant variant in the United Kingdom as Spring 2021. [34]

Previous
Next:

COVID-19 Vaccination While Pregnant or Lactating

According to data from the CDC, 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. [39]  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. [40]  

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. [41]   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. [42]  Collier et al observed binding, neutralizing, and functional nonneutralizing antibody responses, as well as CD4 and CD8 T-cell responses were present in pregnant, lactating, and nonpregnant women following vaccination. Binding and neutralizing antibodies were also observed in infant cord blood and breast milk. Binding and neutralizing antibody titers against the SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern were reduced, but T-cell responses were preserved against viral variants. [43]

Researchers studied placentas of pregnant women vaccinated with mRNA vaccines after delivery. mRNA vaccines induce an immune response through activation of TLR3, which has been linked to decidual arteriopathy, growth restriction, preterm delivery, and fetal loss in mouse models. Placental examination in women with vaccination showed no increased incidence of decidual arteriopathy, fetal vascular malperfusion, low-grade chronic villitis, or chronic histiocytic intervillositis compared with women in the control group. Incidence of high-grade chronic villitis was higher in the control group than in the vaccinated group. [44]

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, because 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

Preliminary findings regarding safety of mRNA COVID-19 vaccines in pregnant females from the CDC v-safe registry did not show obvious safety signals. Additional follow-up, including women vaccinated earlier in pregnancy is needed to determine maternal, pregnancy, and infant outcomes. [45] 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.

Previous
Next:

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) [46]

DNA-based, 2-dose vaccine. Stable at room temperature for more than 1 y; frozen shipment not needed. Phase 2/3 trial (INNOVATE) ongoing; phase 2 to evaluate 2-dose regimen (1 mg or 2 mg) vs placebo in 400 participants.

CVnCoV (CureVac) [47]

mRNA, 2-dose vaccine. Phase 2b/3 trial (HERALD) began in December 2020 of mRNA 12-mcg dose (2 doses on days 1 and 29) in multiple European and Latin American sites with goal to enroll 35,000 participants. Partnering with Bayer, GlaxoSmithKline, and Novartis for production.  
Recombinant protein adjuvanted vaccine (Sanofi and GSK) [48]

Interim phase 2 results (n = 722) showed 95-100% seroconversion after 2 doses with strong neutralizing antibody levels comparable to natural infection. After a single injection, high neutralizing antibody levels were generated in participants with evidence of prior SARS-CoV-2 infection, suggesting strong potential for development as a booster vaccine. Phase 3 trial starting mid-2021 with target enrollment of 35,000.

S-Trimer with CpG 1018 adjuvanted vaccine (Clover and Dynavax) [49]   Phase 2/3 trial (SPECTRA) of Clover’s protein-based S-Trimer COVID-19 subunit vaccine adjuvanted with Dynavax’s CpG 1018 plus alum. Trial began in March 2021 in Latin America, Asia, Europe, and Africa. Administered as 2 doses, 21 days apart. 
VLA2001 with CpG 1018 adjuvant (Valneva and Dynavax) [50]   Inactivated whole virus vaccine. Phase 3 trial (Cov-Compare) in the United Kingdom will compare immunogenicity of VLA2001 with AZD-1222 in ~4,000 adults. 
UB-612 multitope peptide-based vaccine (COVAXX [United Biomedical, Inc]) [51]  

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) [52]   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) [53]   Vaccine prototype development utilizing self-assembling protein nanoparticle (1c-SapNP) vaccine platform technology.
PDA0203 (PDS Biotechnology Corp) [54]   Utilizes Versamune T-cell-activating platform for vaccine development.
CoVLP (Medicago and GlaxoSmithKline) [55]   Combines Medicago’s recombinant coronavirus virus-like particles (rCoVLP) with GSK’s adjuvant system. Phase 3 trial initiated in March 2021 aims to enroll 30,000 healthy adults aged 18-65 y initially, followed by individuals 65 y and older with comorbidities. The trial will take place in 10 countries, initially starting in Canada and the United States. 

Covaxin (BBV152; Bharat Biotech and Ocugen) [56]  

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 after a fully enrolled phase 3 trial (n ~25,800). Interim phase 3 results reported March 2021 in India reported 81% efficacy. Second interim analysis of phase 3 results in late April 2021 found 78% efficacy against mild-to-moderate infection and 100% efficacy against severe COVID-19. Plans to pursue full U.S. approval (biologics license application [BLA]) instead of an EUA upon recommendation from the FDA. 

Recombinant adenovirus type-5-vectored vaccine (Ad5-vectored vaccine; Sinopharm [China]) [57]   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. World Health Organization approved vaccine for emergency use in May 2021 to improve distribution to poorer nations via Covax. 
CoronaVac (Ad5-vectored vaccine; Sinovac [China]) [58]   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) [59] 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 first dose (ie, day of dose 2) confirm COVID-19 infection in 0.1% of the vaccine group compared with 1.3% of the placebo group. Vaccine effectiveness, 91.3%. 
hAd5 T-cell (ImmunityBio and NantKwest) [60]  

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) [61] 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) [62]   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) [63]   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) [64]

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. 
Previous
Next:

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) [60]  

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 1/2 trial studying the safety, reactogenicity, and immunogenicity of a SC and orally administered supplement vaccine to enhance T cell based immunogenicity in patients who already received vaccine authorized for emergency use. 

Intranasal COVID-19 vaccine (AdCOVID; Altimmune, Inc) [65]   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.  
VXA-CoV2-1 oral vaccine (Vaxart) [66]   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. 
Transdermal microneedle COVID-19 vaccines (U of Pittsburgh; U of Connecticut; Vaxess Technologies, Verndari) [67]   Various universities and companies are working with transdermal microneedle delivery for COVID-19 vaccines. 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) [68]   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. 
Triple antigen oral vaccine (Oravax)  Oravax is a collaboration between Premas Biotech and Oramed Pharmaceuticals. Clinical trial planned for mid-2021. 
Oral vaccine (Esperovax)  Gained funding from BARDA for research on oral vaccine platform. 

 

Previous
Next: