COVID-19 Vaccines: Where Are We Now?

Not since the Spanish flu of 1918 has the world experienced such a worldwide outbreak as COVID-19. Declared a pandemic by the World Health Organization (WHO) on March 11, 2020,¹ by April 1, 2021, more than 30 million Americans had contracted the SARS-CoV-2 virus and almost 550,000 Americans had died from it.² Scientists say the only way to halt further global spread of COVID-19 is with a vaccine.

Coronavirus disease of 2019 — or COVID-19 — is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus strain. Because COVID-19 is a novel virus, it is more contagious than other currently circulating viruses because the global population does not have antibodies to fight it. Consequently, the COVID-19 virus has proven to be deadlier than the SARS-CoV-2 outbreak in 2003 and the Middle East respiratory syndrome (MERS-CoV) outbreak in 2012.

In addition to the original COVID-19 virus, there are three variants circulating around the world: B.117 (which originated in the United Kingdom); B.1.351 (which originated in South Africa) and P1 (which originated in Brazil). Therefore, not only do vaccine manufacturers have the daunting task of developing a novel vaccine in record time to prevent further COVID-19 infections, they must also adjust their vaccine formulae or develop new vaccines that will provide efficacy for the emerging variants.

To assist with this unprecedented endeavor, on May 15, 2020, the United States launched Operation Warp Speed (OWS) to accelerate the development, manufacturing and distribution of COVID-19 vaccines. Federally funded with $10 billion, OWS is a partnership among the Department of Health and Human Services, Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), Biomedical Advanced Research and Development Authority and Department of Defense. OWS selected and provided funding to the vaccine manufacturers that had the most promising vaccine candidates.³

Three of the vaccine manufacturers have already received emergency use authorization (EUA) from the U.S. Food and Drug Administration (FDA). However, none of the vaccine candidates have yet received FDA approval or licensing. Even so, CDC, FDA and the vaccine manufacturers all believe the known and potential benefits of these vaccine candidates outweigh the known and potential risks of them.

Two types of COVID-19 vaccines are being developed. Messenger RNA (mRNA) vaccines, made from genetic material that tells a human body how to make proteins, wraps the mRNA in a coating to make delivery easy and keep the human body from damaging it. The mRNA in the vaccine teaches human cells how to make copies of the spike proteins found on the coronavirus so that if a human is exposed to the real virus, the body will recognize it and fight it.⁴

Viral vector vaccines use a harmless version of a different virus, called a “vector,” to deliver information to the human body to help protect itself. These vaccines also teach the human body how to make copies of the spike proteins found on the coronavirus, thereby recognizing the real virus if exposed so it can fight it.⁵

At the time of this writing, six vaccine candidates are most promising.

Pfizer Inc.

On Dec. 11, 2020, FDA issued an EUA for Pfizer-BioNTech’s BNT162b2 COVID-19 vaccine. This vaccine is based on BioNTech’s proprietary mRNA technology, which is a lipid nanoparticle-formulated, nucleoside-modified messenger ribonucleic acid (mRNA) vaccine encoding the prefusion spike glycoprotein of SARS-CoV-2.

Pfizer’s landmark Phase III clinical trial for BNT162b2 was designed as a 1:1 vaccine candidate to a placebo, randomized, observer-blinded study to obtain safety, immune response and efficacy data. The study enrolled 43,448 participants 16 years or older at 150 sites in the United States, Germany, Turkey, South Africa, Brazil and Argentina. Immunization consisted of two doses of the vaccine candidate administered three weeks apart.

The trial’s primary endpoints were the prevention of infection by SARS-CoV-2 in participants who had and had not been previously infected by it prior to immunization. Secondary endpoints included the prevention of severe COVID-19 in both groups. Results showed the vaccine candidate was well-tolerated and demonstrated a vaccine efficacy of 95 percent against COVID-19 in participants without prior infection seven days or more after the second dose. Among participants with and without evidence of prior SARS CoV-2 infection, vaccine efficacy was found to be 94.6 percent.

Data from the study, including longer-term safety, comprehensive information on duration of protection, efficacy against asymptomatic SARS-CoV-2 infection, and safety and immunogenicity in adolescents 12 years to 15 years of age, will continue to be gathered. Pfizer-BioNTech have additional studies planned to evaluate BNT162b2 in pregnant women, children younger than 12 years and those in special risk groups such as the immunocompromised.⁶

Pfizer-BioNTech are also preparing for circulating variants by evaluating a booster dose of BNT162b2. This study will offer participants from the Phase I study in the United States the opportunity to receive a booster of the current vaccine six months to 12 months after receiving their initial two-dose regimen.

The companies are also in discussions with FDA and the European Medicines Agency (EMA) concerning a registration-enabling clinical study to evaluate a variant-specific vaccine that has a modified mRNA sequence. This study will use a new construct of Pfizer-BioNTech’s vaccine based on the B.1.351 lineage that will allow the companies to quickly update their current vaccine from circulating strains.⁷

Real-world evidence of Pfizer-BioNTech’s vaccine from the Israel Ministry of Health shows it dramatically lowers incidence rates of COVID-19 in individuals fully vaccinated. Specifically, evidence shows the vaccine prevents symptomatic infections, cases, hospitalizations, severe and critical hospitalizations and death. Evidence also shows that, two weeks after the second vaccine dose, protection is even stronger, at least 97 percent, in preventing symptomatic illness, severe and critical illness and death, and is at least 94 percent effective against asymptomatic infections.⁸

ModernaTX Inc.

On Dec. 18, 2020, FDA issued an EUA for ModernaTX’s COVID-19 vaccine, formerly known as mRNA-1273. This vaccine, co-developed by Moderna and the National Institute of Allergy and Infectious Disease’s Vaccine Research Center, also uses the mRNA vaccine technology.

Moderna’s Phase III clinical trial, also known as the COVE study, was a randomized, 1:1 placebo-controlled study that enrolled more than 30,000 participants 18 years or older in the United States. The study included participants at high risk of severe complications from COVID-19, with more than 7,000 Americans over age 65 years. The study also included more than 5,000 Americans under age 65 years who had high-risk chronic diseases such as diabetes, severe obesity and cardiac disease that increased their risk of severe COVID-19. These medically high-risk participants represented 42 percent of the total participants. Most participants (82 percent) were considered to have had an occupational risk of exposure since 25.4 percent of them were healthcare workers. Immunization consisted of two doses of the vaccine candidate administered 28 days apart.⁹

The COVE study’s primary endpoint was prevention of symptomatic COVID-19, and key secondary endpoints included prevention of severe COVID-19 and prevention of infection by SARS-CoV-2. Results showed the vaccine exhibited favorable tolerability and safety and a vaccine efficacy of 94.1 percent against COVID-19.9

This study is ongoing, and additional data collection will include longer-term safety follow-up, duration of protection against COVID-19, and efficacy against asymptomatic SARS-CoV-2 infection. Moderna is also conducting a Phase II/III study of its vaccine in adolescents 12 years to 18 years, children younger than 12 years, pregnant women and people who are immunocompromised.¹⁰

Moderna recently enrolled 60 participants previously vaccinated with mRNA-1273 in Phase II to evaluate booster vaccine candidates against the B.1.351 variant first identified in South Africa. This booster vaccine, mRNA-1273.351, is a single vaccine designed to elicit a broad immune response as both a primary series and when administered as a boost to those who have previously received mRNA-1273.¹¹

Moderna’s Phase II/III two-part, open label, dose-escalation, age de-escalation (Part 1) and randomized, observer-blind, placebo-controlled expansion KidCOVE study (Part 2) will evaluate the safety, tolerability, reactogenicity and effectiveness of two doses of mNRA-1273 administered 28 days apart. It will enroll approximately 6,750 pediatric participants in the United States and Canada aged 6 months to less than 12 years.¹²

Janssen Pharmaceutical Companies of Johnson & Johnson

In February 2021, FDA issued an EUA for Janssen Pharmaceutical Companies of Johnson & Johnson’s Ad26.COV2.S vaccine, also known as JNJ-78436735, which uses the company’s AdVac viral vector vaccine platform.¹³

Janssen’s Phase III ENSEMBLE study was a randomized, double-blind, placebo-controlled clinical trial that enrolled approximately 45,000 participants 18 years and older, and included a diverse and broad population, including 34 percent of participants older than 60 years. The study, conducted in eight countries on three continents, was designed to evaluate the efficacy and safety of the vaccine to protect moderate to severe COVID-19, with co-primary endpoints of 14 days and 28 days following vaccination. Among all participants from different geographies, including participants infected with an emerging viral variant, the vaccine was 66 percent effective overall in preventing moderate to severe COVID-19 28 days after vaccination, with the onset of protection observed as early as day 14. The level of protection against moderate to severe COVID-19 infection was 72 percent in the United States, 66 percent in Latin America and 57 percent in South Africa 28 days postvaccination. 

In addition, the vaccine was 85 percent effective in preventing severe illness across all regions 28 days after vaccination in all adults 18 years and older. Efficacy against severe illness increased over time, with no cases in vaccinated participants reported after day 49. The vaccine also demonstrated complete protection against COVID-related hospitalization and death 28 days postvaccination. And, there was a clear effect of the vaccine on COVID-19 cases requiring medical intervention (hospitalization, ICU admission, mechanical ventilation, extracorporeal membrane oxygenation), with no reported cases among participants who had received the vaccine.

Finally, protection was generally consistent across race, age groups (including adults over 60 years) and all variants and regions, including South Africa where nearly all cases of COVID-19 (95 percent) were due to infection with a SARS-CoV-2 variant from the B.1.351 lineage.

The ENSEMBLE study results also included efficacy against newly emerging strains of coronavirus, including some highly infectious variants present in the United States, Latin America and South Africa. ENSEMBLE was conducted at the height of the COVID-19 pandemic, at a time when spread of the virus had accelerated throughout the world, resulting in people having increased exposure to the virus.

Janssen is also investigating immune responses for different doses and dosing regimens, as well as a two-dose regimen spaced two months apart, of its COVID-19 vaccine for efficacy in its ENSEMBLE 2 study. This second study will investigate if a second dose might provide greater or longer protection. Results are expected to be available in the second half of 2021.¹⁴ Johnson & Johnson is planning to file a biologics license application with FDA later in 2021.

 On April 9, 2021, EMA reported it was reviewing reports of rare blood clots in four people who received Johnson & Johnson’s COVID-19 vaccine. Of the four serious cases of clotting and low platelets, three occurred in the United States during the rollout of the vaccine from its Janssen unit, and one person died during a clinical trial. The company said it was aware of the reports of blood clots possibly related to its vaccine and others, and it is working with regulators to assess the data and provide relevant information.¹⁵ On April 13, 2021, FDA advised states to pause use of the Johnson & Johnson vaccine to investigate reports of potentially dangerous blood clots. However, the vaccine is once again being administered in the U.S.

Oxford-AstraZeneca

In collaboration with the University of Oxford, AstraZeneca is investigating its COVID-19 vaccine, formerly AZD1222, which uses the viral vector technology platform.

Results from AstraZeneca’s Phase III study, called D8110C00001, showed its vaccine is 76 percent effective at preventing symptomatic COVID-19, 100 percent effective against severe or critical disease and hospitalization, and 85 percent effective against symptomatic COVID-19 in participants aged 65 years and older.¹⁶

This study was based on 32,449 participants at 88 trial centers in the United States, Peru and Chile. Participants were 18 years or older, with approximately 20 percent of them 65 years and older and approximately 60 percent who had comorbidities associated with an increased risk for progression of severe COVID-19. Participants were administered two doses of the vaccine at a four-week interval. Previous trials showed an extended interval of up to 12 weeks demonstrated greater efficacy, which was also supported by immunogenicity data, suggesting administration of the second dose with an interval longer than four weeks could further increase efficacy and accelerating the number of people who can receive their first dose. AstraZeneca will now prepare for its primary analysis to be submitted to FDA for EUA.¹⁷

On April 6, 2021, EMA said there is a “clear” link between AstraZeneca’s vaccine and rare blood clots in the brain. However, the agency stressed that the benefits of the vaccine still outweigh any possible risks, a line EMA, WHO and a number of other regulators have held while many European countries suspended or restricted the use of the vaccine. Because the clotting seems to be of most concern in younger people, a number of countries, including France and Germany, are restricting the vaccine to older populations. In late March, Canada paused vaccination for those under 55 years, citing a risk of blood clots. And, the United Kingdom’s medicines regulator is reportedly considering offering those under 30 years different vaccines after 30 cases of rare blood clots were linked to the shot.¹⁸

AstraZeneca is also working on a COVID-19 treatment, a long-acting antibody (LAAB) combination called AZD7442, engineered with the company’s proprietary half-life extension technology to increase the durability of the therapy for six months to 12 months following a single administration. The combination of two LAABs is also designed to reduce the risk of resistance developed by the SARS-CoV-2 virus.

LAABs mimic natural antibodies and have the potential to treat and prevent disease progression in patients already infected with the virus. They can also be given as a preventive intervention prior to exposure to the virus. Discovered by Vanderbilt University and licensed to AstraZeneca in June 2020, the antibodies were optimized by AstraZeneca with half-life extension and Fc receptor binding reduction. The LAAB has been shown preclinically to block the binding of the SARS-CoV-2 virus to host cells and protect against infection in cell and animal models of disease.¹⁹

AZD7442 is currently being assessed in five late-stage prevention and treatment trials. The Phase III trial, STORM CHASER, started in December 2020 and is assessing the safety and efficacy of AZD7442 compared to placebo for the prevention of COVID-19 in approximately 1,125 participants after exposure to a specific identified individual with laboratory-confirmed SARS-CoV-2 infection (postexposure prophylaxis).

The Phase III PROVENT trial started in November 2020 and is assessing the safety and efficacy of AZD7442 compared to placebo for the prevention of COVID-19 in approximately 5,000 adults who are at increased risk for SARS-CoV-2 infection due to living or work situations, or who are at increased risk of responding inadequately to vaccines such as those who have compromised immune systems.

Both the STORM CHASER and PROVENT trials are being held at the Vaccine Research Centre at University College London Hospitals in the United Kingdom.

An AstraZeneca-sponsored Phase III TACKLE COVID-19 trial that started in January 2021 is evaluating the safety and efficacy of AZD7442 compared to placebo in treating nonhospitalized patients with mild to moderate COVID-19.

AZD7442 is also being studied as a potential treatment as part of NIH’s Phase II/III ACTIV-2 (outpatient) and ACTIV-3 (hospitalized) trials, both of which started in February 2021.

Novavax Inc.

Novavax Inc. is investigating its COVID-19 vaccine candidate, NVX-CoV2373, which was developed using the company’s recombinant nanoparticle technology to generate antigen derived from the genetic sequence of the coronavirus spike protein and is adjuvanted with Novavax’s patented saponin-based Matrix-M.

The vaccine is in two Phase III clinical trials. The first is being conducted in the United Kingdom, which enrolled more than 15,000 participants between 18 years and 84 years old, including 27 percent over age 65. Results showed a vaccine efficacy of 96.4 percent against the original virus and 89.4 percent in more than 50 percent of cases attributable to the variant that is now predominant in the United Kingdom. In this trial and a Phase IIb trial, NVX-CoV2373 provided 100 percent protection against severe illness.²⁰

The second study, the PRE-fusion protein subunit Vaccine Efficacy Novavax Trial, or PREVENT-19, is a randomized, placebo-controlled, observer-blinded study in the United States and Mexico that finished enrolling 30,000 participants aged 18 years and older in February 2021 to evaluate the efficacy, safety and immunogenicity of NVX-CoV2373. Two-thirds of participants have been assigned to randomly receive two intramuscular injections of NVX-CoV2373 21 days apart, while one-third of participants will receive a placebo.

After efficacy is determined, participants will remain eligible for a crossover arm of the trial, during which they will be given the opposite (active vaccine or placebo) of what they originally received. Depending on the results, Novavax was expecting to file an EUA with FDA in the second quarter of 2021.²¹

The Phase IIb trial, conducted in South Africa, enrolled more than 4,400 patients. Results showed an efficacy of 55 percent for the prevention of mild, moderate and severe COVID-19 that was observed in 94 percent of the study population that was HIV-negative. This study took place in a region where the vast majority of strains are B1.351 escape variants that contain three critical mutations in the receptor binding domain (RBD) and multiple mutations outside the RBD.²⁰

Novavax initiated development of constructs against the various strains of SARS-CoV-2 in January 2021 and expects to select ideal candidates for a booster and/or combination bivalent vaccine against the B1.351 strain soon. The company is conducting preclinical testing and was expected to be in human testing in the second quarter of 2021.²²

Sanofi-GSK and Sanofi-Translate Bio

In collaboration with GlaxoSmithKline (GSK), Sanofi Pasteur is investigating two vaccine candidates for COVID-19, a recombinant protein-based vaccine that uses its recombinant antigen and GSK’s pandemic adjuvant, both of which are established vaccine platforms proven successful against influenza. The combined platforms provide the advantages of stability at temperatures used for routine vaccines, the ability to generate high and sustained immune responses, and the potential to prevent virus transmission.

In February 2021, Sanofi-GSK announced a new Phase II clinical trial, a randomized, double-blind, multi-center dose-finding study to evaluate the safety, reactogenicity and immunogenicity of two injections given 21 days apart. Three different antigen doses with a fixed dose of adjuvant will be tested in a total of 720 participants aged 18 years and older, with equal numbers of participants aged 18 years to 59 years and participants 60 years and older in the United States and Honduras.

If data from this study are positive, a global Phase III study is planned for the second quarter of 2021. Positive results from the Phase III study would lead to regulatory submissions in the second half of 2021, with the vaccine expected to be available in the fourth quarter of 2021, if approved.

With the emergence of new SARS-CoV-2 variants and their potential impact on vaccine efficacy, in parallel to this new Phase II study, Sanofi has commenced work against new variants that will be used to inform next stages of the Sanofi-GSK development program.²³

Sanofi is also working in partnership with Translate Bio to develop an mRNA-based vaccine candidate called MRT5500. Encouraging preclinical data showed two immunizations of the mRNA vaccine induced high neutralizing antibody levels that are comparable to the upper range of those observed in infected humans.

In March 2021, Sanofi announced the start of its Phase I/II randomized, double-blind and placebo-controlled study of MRT5500 to evaluate its safety, reactogenicity and immunogenicity. A total of 415 healthy participants aged 18 years and older will be enrolled in the trial at 13 sites. Participants will receive one dose of MRT5500, or two doses 21 days apart, with three different doses given. Interim results are expected in the third quarter of 2021^.24

Looking Ahead

Despite these extraordinary vaccine developments, even as vaccine manufacturers receive EUAs from FDA for their vaccine candidates, and hundreds of millions of individuals are ultimately vaccinated, these vaccines will not completely eradicate the COVID-19 virus. The reasons are many, including the inability of everyone to receive a vaccine and vaccine-hesitancy. It’s possible herd immunity might not be achieved, and the COVID-19 virus will continue to circulate around the globe, albeit not necessarily at a pandemic level. Scientists believe the CVOID-19 virus might eventually become part of our annual cold and flu season.

Furthermore, when a vaccine receives EUA from FDA, it does not mean the vaccine is approved or licensed. Vaccine manufacturers still need to file for a biologics license application with FDA for their vaccines to receive official approval and licensing.

Another caveat: After vaccine manufacturers have received EUA from FDA for their vaccines, they are required to monitor Phase III participants for at least two years after they have received their first and/or second dose of the vaccine. Data from this two-year period are submitted to FDA for review and approval as part of the vaccine licensing process.

In addition, vaccine manufacturers state their vaccines do not have 100 percent efficacy. Their vaccines may not provide protection for all vaccinated individuals, they do not know the length of their vaccines’ efficacy, and they do not know if their vaccines will provide protection for all the variants currently circulating or new ones that have yet to emerge.

Vaccine manufacturers also state individuals should not receive their vaccines if they are under 12 years, have received another COVID-19 vaccine (since it is currently unknown if vaccines are interchangeable), have severe allergies (specifically to ingredients in the mRNA vaccine’s formula) and/or are immunocompromised.

A recent cohort study published in the American Journal of Obstetrics & Gynecology showed the Pfizer and Moderna vaccines are safe for pregnant and lactating women. According to the study’s authors, “Pregnant and lactating women elicited comparable vaccine-induced humoral immune responses to nonpregnant controls, and generated higher antibody titers than those observed following SARS-CoV-2 infection in pregnancy. Vaccine-generated antibodies were present in umbilical cord blood and breastmilk after maternal vaccination.” Additional studies will be needed for the Johnson & Johnson (Janssen) and AstraZeneca vaccines to determine if they are also safe for pregnant and lactating women.²⁵

It should be noted the Spanish flu pandemic lasted for two years with four waves. To date, the COVID-19 pandemic has lasted approximately one-and-a-half years with three waves. If history repeats itself, the global population can expect the COVID-19 pandemic to continue at least another six months with at least one more wave. Ultimately, only time will tell if these COVID-19 vaccines, after they are approved and licensed, will become part of the world’s regular vaccination programs.