COVID-19 Vaccine Research Brief

11/19/21 - The section on the covaxin vaccine was updated to reflect new preliminary findings (see Bharat Biotech)

11/10/21 - A section on booster doses was added (see Booster Doses)

10/26/21 - The section Vaccine Safety was updated to reflect new findings on the risk of adverse outcomes from COVID-19 vaccination among pregnant women (see Vaccine Safety). The section on Vaccine Allocation was updated to reflect new findings on the impact of vaccine mandates (see Vaccine Allocation)

7/30/21 - A section on breakthrough cases was added (see Breakthrough Cases)

5/14/21 - The section Vaccine Safety was updated to reflect new findings on the immunogenicity following mRNA vaccination in pregnant and lactating women (see Vaccine Safety)

4/21/2021 - The section Johnson & Johnson was updated to reflect a joint statement issued by CDC and FDA (see Johnson & Johnson)

VACCINES FOR COVID-19

Globally, as of January 14, 2021, there are 20 vaccines are in phase 3 trials, with 8 vaccines approved for limited use and 2 vaccines approved for full use in the United States.¹

Navigate this resource by topic:

I. TABLES 
     a. Approved Vaccines in the United States
     b. Internationally Approved/Limited Use/ Early Use Vaccines
     b. Vaccines in Clinical Trials

II. APPROVED VACCINES FOR COVID-19
     a. Pfizer and BioNTech
     b. Moderna

III. VACCINES APPROVED OUTSIDE THE UNITED STATES
     a. Sinopharm and Beijing Institute of Biological Products
     b. Covaxin
     c. AstraZeneca

IV. APPROVED FOR LIMITED OR EARLY USE
     a. Cansino Biologics
     b. Sinopharm and Wuhan Institute of Biological Products
     c. Sinovac Biotech
     d. Gamaleya Research Institute
     e. Vector Institute

V. VACCINES IN PHASE 3 CLINICAL TRIALS
     a. JohnsonJohnson
     b. CureVac
     c. Novavax
     d. Anhui Zhifei Longcom
     e. Institute of Medical Biology and the Chinese Academy of Medical Sciences
     f. Zydus Caila
     g. Research Institute for Biological Safety Problems

VI. VACCINES IN PHASE 2/3 CLINICAL TRIALS
     a. Medicago

VII. VACCINE DISTRIBUTION
     a. Pfizer and BioNTech
     b. Moderna

VIII. VACCINE ALLOCATION

IX. VACCINE SAFETY

X. VACCINE DEVELOPMENT DISCONTINUATION

XI. COVID-19 VARIANTS

XII. CDC VACCINE SCHEDULE RECOMMENDATIONS

XIII. BREAKTRHOUGH CASES

XIV. BOOSTER DOSES

XV. REFERENCES

Tables

Table 1. Vaccines Approved in the United States

 Table 2. Internationally Approved/Limited Use/Early Use Vaccines

Table 3. Vaccines in Clinical Trials

Approved

Pfizer and BioNTech

Pfizer is collaborating with BioNTech SE and Fosun Pharma for its 2-dose mRNA vaccine.^1,2 Like Moderna, Pfizer began its phase 3 trial in July 2020 after testing several vaccine versions. The company chose BNT162b2 since it had significantly fewer side effects and produced antibodies and T cells in response. The trial had been initially scheduled for 30,000 participants globally, but that number was increased to 44,000 in September 2020.² As of August 20, 2020, 11,000 participants had been enrolled and in September Pfizer announced their intent to expand the trial to 43,000 participants.³ In October, Pfizer and its collaborators initiated a rolling submission to the European Medicines Agency following what the companies said were encouraging preliminary results.⁴ On November 9, 2020, Pfizer announced that the results of the first interim efficacy analysis of results from the phase 3 trial showed vaccine efficacy of "more than 90%."⁵ On November 18, 2020, Pfizer and BioNTech officially announced that the vaccine is 95% effective⁶ and submitted a request for an emergency use authorization 2 days later on November 20, 2020.¹

On December 2, 2020, the United Kingdom became the first Western country to approve a coronavirus vaccine when it issued an emergency authorization to Pfizer and BioNTech’s vaccine.¹ The United States followed soon after; on December 11, 2020, the FDA granted a EUA to Pfizer for their vaccine to prevent COVID-19 in persons aged 16 years and older.⁷ Pfizer has reported common side effects of injection site pain, tiredness, headache, muscle pain, joint pain, and fever, all of which typically only lasted a few days. Pfizer stated that most adverse effects were experienced following the second dose as opposed to the first.⁷

At the end of December 2020, the World Health Organization granted an emergency use listing to the vaccination. This designation allows for the quicker authorization of the vaccine in other countries.¹

On September 22, 2021, the US Food and Drug Administration authorized a booster dose of the Pfizer-BioNTech COVID-19 vaccine for certain patient populations. Eligible individuals include those aged 65 years or older and those aged 18 to 64 who are at high risk of severe disease or serious complications due to institutional or occupational exposure.⁶¹

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Moderna

Moderna, collaborating with the National Institute of Allergy and Infectious Diseases, produced vaccine candidate mRNA-1273.⁸ The vaccine uses messenger RNA (mRNA), teaching it to produce viral proteins and allowing the immune system to build up antibodies against the novel coronavirus. The vaccine entered phase 3 clinical trials in July 2020, enrolling 30,000 healthy volunteers in the United States. The vaccine requires 2 doses a few weeks apart.⁸ The vaccine candidate was 94.5% effective in a recent trial.⁹

Moderna applied to the FDA for an emergency use authorization on November 30, 2020.¹ On December 18, 2020, the FDA issued a EUA to Moderna.¹⁰ All 11 members of the Advisory Committee on Immunization Practices (ACIP) voted in favor of the Moderna vaccine.¹¹This authorization is for patients 18 years of age and older.¹⁰ Moderna is the second COVID-19 vaccine to be granted EUA status, following the approval of Pfizer at the beginning of December 2020. The most common side effects reported during studies were injection site pain, tiredness, headache, muscle pain, chills, joint pain, swollen lymph nodes in the same arm as the injection, nausea, and vomiting, and fever. Most patients experienced adverse reactions following the second dose of the vaccine. ¹⁰

Moderna plans to deliver at least 20 million doses to the United States government by the end of December 2020 to be distributed by Operation Warp Speed.¹¹ In the first quarter of 2021 Moderna expects to produce 100 million to 125 million doses, 85 million to 100 million of which will be available within the United States.¹¹

On January 6, 2021, the European Medical Agency authorized the use of the Moderna vaccine in the European Union.¹

On October 20, 2021, the US Food and Drug Administration authorized a booster dose of the Moderna COVID-19 vaccine in certain populations under an emergency use authorization. Eligible individuals include those aged 65 years or older or those aged 18 to 64 who are at high risk of severe disease or have frequent exposure to SARS-CoV-2 through their institutions or occupations.⁶²

Johnson & Johnson

Johnson & Johnson’s candidate is made from the human adenovirus 26 (Ad26), previously used as a vaccine platform for Ebola, respiratory syncytial virus (RSV), Zika, and HIV.¹² The Ebola vaccine recently received European Commission marketing authorization.¹³ Ad26, which causes the common cold, will deliver part of the novel coronavirus spoke protein into cells, stimulating antibody production.

The phase 3 trial began in September 2020, with the goal of enrolling 60,000 volunteers globally.¹⁴ The phase 2 study showed that 1 dose simulated a robust immune response with relatively few side effects, making it unique in its potential 1-dose delivery.¹⁵ Interim results of a Phase 1/2a trial were published on January 13, 2021. Cohort 1 consisted of 402 individuals who received the first dose of the vaccine and Cohort 3 consisted of 403 individuals. Between the two cohorts, following the first dose of vaccine, most systemic adverse effects were grade 1 or 2 with the most frequently reported adverse effects being headache, fatigue, and myalgia.¹⁶ No participants discontinued the trial due to severe adverse events. Participants who received the higher vaccine dose experienced an increase in adverse systemic effects following the first dose.¹⁶

The phase 3 trial will be double-blind, with half of the participants getting a placebo. The investigators will gauge effectiveness by whether the experimental vaccine prevents 60% of infections compared with placebo. They anticipate a verdict after 154 study volunteers get sick from the virus in their normal daily course but will evaluate effectiveness after 20 subjects get infections.¹⁷ Johnson & Johnson will also run a smaller double-dose trial. On November 16, 2020, it was announced that this plan was expanded to launching a second Phase 3 trial to observe the effects of two doses.¹ The vaccines will need refrigeration but not subzero temperature storage, unlike the Pfizer and Moderna vaccines, which need to remain frozen.¹⁸ On October 12, 2020, the company put the trial on pause due to an adverse reaction in a volunteer; the trial then resumed 11 days later. Despite the delay, the company still expects to have results by the end of the year.¹

On January 29, 2020, the National Insitutes of Health issued a news release regarding results of the Phase 3 clinical trial of the Janssen Pharmaceutical Companies of Johnson & Johnson's COVID-19 vaccine. Interim analysis of the data demonstrated both safety and efficacy at preventing moderate to severe COVID-19 in adults.¹⁹  Of the 44,435 volunteers who received the vaccine, there were 468 cases of symptomatic COVID.¹⁹ The vaccine was 66% at preventing the development of moderate to severe COVID 28 days following vaccination.¹⁹ The vaccine, Ad.26.COV2.S is a single dose injection which can be stored in the refrigerator.¹⁹ 

Johnson & Johnson submitted an EUA to the FDA on February 4, 2021 for their single-dose COVID-19 vaccine.²⁰ The submission cites data from the Phase 3 clinical trial (ENSEMBLE) which met all primary and secondary endpoints.²⁰ Should the vaccine be approved, Johnson & Johnson intends to distribute 100 million doses within the US in the first half of 2021 and believes they can ship vaccines out immedlity following approval.²⁰

The FDA granted an EUA to the Janssen Johnson & Johnson COVID-19 vaccine on February 27, 2021.²¹ The decision was based upon all available data, which demonstrated clear evidence that the vaccine is effective at preventing COVID-19 and that the benefits outweigh the potential risks in persons aged 18 and older.²¹ Unlike the two previously approved vaccines, mRNA vaccines, the Johnson & Johnson vaccine is a viral vector which allows for standard vaccine storage and distribution channels.²² This will create an ease of delivery to remote areas as the vaccine is stable for 3 months at temperatures of 36 to 46 degrees Farenheit.²²  

The World Health Organization (WHO) released interim recommendations for the use of the Johnson & Johnson vaccine on March 17, 2021.⁵³ The Strategic Advisory Group of Experts (SAGE), recommends for the use of the Johnson & Johnson AD26.COV2.S vaccine as their is an urgen global need for safe and effective vaccines.⁵³ The vaccine is recommended for individuals age 18 years and above, given in a 1 dose series without a need for a booster dose.⁵³ A single dose of the vaccine has efficacy of 66.9% agaist symptomatic COVID-19 infection and 76.7% efficacy against severe COVID-19 infection after 14 days and 85.4% efficacy after 28 days.⁵³ Data are still being collected regarding vaccination in pregnant women, but in the interim WHO states that pregmant women should only recieve Ad26.COV2.S only if the benefit outweighs the risk.⁵³

On April 13, 2021, CDC and FDA released a joint statement regarding the six reported cases of severe blood clots following vaccination with the Johnson & Johnson vaccine.⁵⁶ The six cases of these rare blood clots, cerebral venous sinus thrombosis (CVST), occured all in women aged 18 to 48 within 6 to 13 days following vaccination.⁵⁶ Treating a CVST is unqiue; in a typical setting heparin is used to treat clots but in this setting heparin administration can be very dangerous.⁵⁶ CDC is pausing administration of the Johnson & Johnson vaccine until the Advisory Committee on Immunization Practice can convene and review the data.⁵⁶ 

On October 20, 2021, the US Food and Drug Administration authorized a booster dose of the Johnson & Johnson COVID-19 vaccine in certain populations under an emergency use authorization. Eligible individuals include those aged 18 years or older who have completed the primary vaccine series at least 2 months prior.⁶²

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Approved Outside the United States

Sinopharm and Beijing Institute of Biological Products

Sinopharm, a state-owned Chinese company, is partnering with the Beijing Institute of Biological products to create BBIBP-CorV.¹ Initial Phase 1/2 clinical trials did not indicate any potentially serious side effects and confirmed the production of antibodies against COVID-19.¹ Beginning in July, the United Arab Emirates was the site of a Phase 3 trial which then expanded to Morocco and Peru. Results of this trial have not yet been released.¹

On September 14, 2020, the United Arab Emirates issued emergency approval to BBIBP-CoV in the use of healthcare workers. Two months later in early December, the vaccine was issued full approval following reports of 86% efficacy.¹ A few days later after the U.A.E announced its approval of BBIBP-CoV, Bahrain announced they were approving the vaccine as well.¹ Following the release of the efficacy data at the end of December 2020, the Chinese government granted approval to BBIBP-CorV.¹

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Bharat Biotech

Covaxin, or BBV152 A, B ,C, is being developed by Bharat Biotech in collaboration with the Indian Council of Medical research.¹ This was the first Indian produced vaccine to advance to clinical trials in June of 2020. Results from the phase 1/2 trials are not yet available, but it has been reported that the vaccine was 85% to 90% effective.¹ Phase 3 trials began on October 23, 2020, and results are expected in early 2021 with plans to roll out the vaccine in June 2021.¹ Bharat Biotech and Pennsylvania-based company Ocugen entered into a partnership on December 22, 2020 to distribute Covaxin within the United States.¹ Covaxin is currently not approved in the United States, nor is it being reviewed by the FDA for emergency use authorization. On January 3, 2021, Covaxin was granted emergency authorization by the Indian Government. However, this use authorization comes without safety or efficacy data as results are yet to be published from the Phase 3 clinical trial.¹

Interim findings from the phase 3 clinical trial revealed that full vaccination with the covaxin vaccine provides protection against symptomatic COVID-19 in 77.8% of cases. Included in the trial were 25,798 adults aged 18 years or older from 25 hospitals in India. Participants were randomly assigned the two-dose regimen, 28 days apart (n = 12,221) of covaxin vaccine or placebo (n = 12,198). The number of positive cases following vaccination was 24, while the number of positive cases following placebo was 106. One serious adverse event or death was reported in the vaccine group. Adverse events such as headache, fatigue, fever, and pain at injection site were reported in 12% of participants within 7 days of administration.⁶⁴

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AstraZeneca

AstraZeneca, collaborating with Oxford University, entered global phase 3 trials of AZD1222 in April 2020.³ The 2-dose vaccines are based on a chimpanzee adenovirus, ChAdOx1. The vaccine is designed to bring the coronavirus genes into human cells, activating an immune response to the novel coronavirus. The trial will enroll 30,000 patients, with 20,000 receiving the investigational vaccine,²³ and as of mid-September 2020, approximately 18,000 patients had been vaccinated.²³ The trial will be considered a success if the vaccine has 50% effectiveness, confirming at least 150 people infected with SARS-CoV-2 for those receiving placebo or AZD1222 inoculations.²³ On November 19, 2020, researchers published the first results from the United Kingdom. The early findings did not indicate any serious side effects between the different age groups, 18 to 55 years old, 56-69 years old, and 70 years and older.¹ On November 23, 2020, the company announced the vaccine demonstrated good efficacy as demonstrated by 131 cases of COVID-19 in trials in the United Kingdom and Brazil.¹

The AstraZeneca trial was paused twice after two British participants experienced neurological illnesses, both potentially transverse myelitis. The first participant was later thought to have previously undiagnosed multiple sclerosis, and the second participant has not been diagnosed. The trials resumed in several countries, including the United States.^23,24

The AstraZeneca vaccine candidate does not have much storage and distribution information currently. Pending stability studies, it is estimated the vaccine will be stored and transported at temperatures of 2° to 8° Celsius.²⁵ The vaccine is stable in the refrigerator for up to 6 months.¹

The United Kingdom's government approved the AstraZeneca vaccine for emergency use on December 30,2020.²⁶ Argentina granted emergency authorization on the same day and India followed a few days later, granted approval of a version called Covishield on January 3, 20201.¹ AstraZeneca plans to begin vaccine roll out to the U.K. public at the beginning of January.²⁷ Pascal Soriet, the chief executive for AstraZeneca, has stated that the vaccine may be effective against the new COVID-19 variant, but further tests are needed.²⁶ This new variant is reported as more transmissible and has resulted in travel restrictions to and from the United Kingdom.²⁷

On February 3, 2021 AstraZeneca released the primary analysis of the Phase III Clinical trial in the Lancet as a preprint. The results from the trial demonstrated that the vaccine is both safe and effective.²⁸ The vaccine is 76% effective after the first dose.²⁸ An inter-dose interval of 12 or more weeks increased vaccine efficacy to 82%.²⁸ One difference between the AstraZeneca vaccine and other approved vaccines is that the AstraZeneca vaccine may reduce transmission in asymptomatic individuals. Positive COVID-19 PCR test readings decreased by 67% following the first dose and 50% after completing the series.²⁸ AstraZeneca announced they are seeking an Emergency Use Lisitng status from the World Health Organization in order to establish a program to provide the vaccine in low-income countries.²⁸ 

On February 15, 2021, World Health Organization listed two versions of the AstraZeneca/Oxford COVID-19 vaccine for emergency use, allowing them to be distributed globally.⁵² The review occurred on February 8, 2021 by WHO’s Strategic Advisory Group of Experts on Immunization (SAGE), who recommended the vaccine for use in patients aged 19 years and older.

WHO released a statement on March 17, 2021 regarding the safety of the AstraZeneca COVID-19 vaccine.⁵⁴ Several countries within the European Union (EU) have suspended the use of the AstraZeneca vaccine for the time being. This decision is a precautionary measure as a result of reports of rare blood coagulation disorders in indivudals who have received the vaccine.⁵⁴ Other EU countries, aware of the reports, have made the decision to continue vaccination with the AstraZeneca vaccine. WHO reports it is in contact with the European Medicines Agency and other global regulators to stay up to date on COVID-19 vaccine safety.⁵⁴ The Subcommittee of the Global Advisory Committee on Vaccine Safety are moniroting the situation and conducting a review, and once complete, WHO will make the findings public. Currently, WHO still considers the benefits to outweigh the risks of the AstraZeneca vaccine.⁵⁴ 

The National Institute of Allergy and Infectious Diseases (NIAID) released a statement on March 23, 2021 regarding the AstraZeneca COVID-19 vaccine.⁵⁵ The Data and Safety Monitoring Board (DSMB) had notified NIAID, the Biomedical Advanced Research and Development Authority (BARDA), and AstraZeneca it was concerned about data from the initial AstraZeneca COVID-19 vaccine trial.⁵⁵ Per the DSMB, concern excists over what data was included from the trial (possibly outdated), which would provide an incomplete view of efficacy data of the vaccine.⁵⁵ NIAID is urging AstraZeneca to work with DSMB to review the data, ensuring that the most up-to-date and accurate data is available.⁵⁵

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Approved for Limited or Early Use

A few vaccines outside the United States have been approved for limited or early use. They include the following:

CanSino Biologics

This Chinese vaccine is based on adenovirus 5 (Ad5) and was approved by the Chinese military for 1 year for its own use. CanSino began phase 3 trials in several countries in August 2020, with an estimated enrollment of 40,000 participants.^1,29 Phase 2 data from 508 patients showed safety and significant immune response, mostly after a single immunization.³⁰ CanSino began conducting phase 3 trials in August in several countries, including Saudi Arabia, Pakistan, and Russia.¹

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Sinopharm and Wuhan Institute of Biological Products

In addition to partnering with the Beijing Institute, Sinopharm is also working with the Wuhan Institute.¹ The partnership is developing an inactive virus that showed the production of antibodies in Phase 1/2 trials.¹ Within the trials fever and other side effects were reported, but no serious adverse effects were observed. Phase 3 trials are currently being carried out in various countries. On December 12 Peru, one of the countries conducting a Phase 3 trial, announced that the trial had been put on hold due to neurological problems observed in one of the study participants.¹ It has not been reported which of the two Sinopharm vaccines the participant received.¹

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Sinovac Biotech

CoronaVac was developed by Sinovac, a private Chinese company.¹ The Phase 1/2 trials did not find any serious adverse effects and immune response was reported. Results from the trial were published in November.¹ Based on immunogenicity production; the study determined that 3 mg was the recommended dose to use in Phase 3 trials.³¹ This Chinese company launched a phase 3 trial in several countries in July 2020 for an inactivated vaccine named CoronaVac.¹The Chinese government reportedly gave emergency approval for limited use in July 2020.¹

In October, Brazil stated that the Sinovac vaccine was the most effective of the 5 that were being tested in Phase 3 trials in Brazil.¹ One month later in November, Brazil announced that the trial was paused due to adverse effects. No further information was given, and the trial was then resumed two days later.¹ In January, researchers from the Brazil trial announced that the vaccine had an efficacy of 50.38%, which is the minimum threshold required by most regulatory agencies approving COVID-19 vaccines.1

Indonesia granted emergency authorization to Coronovac on January 11, 2021, and Turkey followed two days after on January 13, 2021.¹   

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Gamaleya Research Institute

The Russian health ministry institute began trials with 76 participants in June 2020 of Gam-COVID-Vac, which combines Ad5 and Ad26 and is engineered with the SARS-CoV-2 gene.¹ The investigators concluded that it was safe and induced strong immune responses in all healthy participants.³² It was approved in August under the name Sputnik V prior to the beginning of phase 3 trials. The Russian government later said that the approval was conditional on positive results. The trial will enroll 40,000 participants, up from the initial plan of 2000.^1,33

On December 14, 2020, the institute announced that the vaccine had an efficacy rate of 91.4%.¹ The Gamaleya Institute joined with AstraZeneca in December, the two teams will be combining their prospective vaccines to see if the combination would increase protection. The companies aim to start a trial by the end of 2020.¹

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Vector Institute

The Vector Institute, a Russian Biological center, is developing EpiVacCorona which contains a small portion of peptides.¹ Phase 1/2 trials began in August of 2020 and by October 14, 2020, Vladimir Putin announced that EpiVacCorona was granted regulatory approval. Like the Sputnik V vaccine developed by the Gamaleya Research Institute, EpiVacCorona received approval before any phase 3 trials were conducted to ensure safety and efficacy.¹

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Vaccines in Phase 3 Clinical Trials

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CureVac

CVnCOV, developed by the German company CureVac, began clinical trials in July.1 As of December, CureVac launched a Phase 3 trial of 36,5000 volunteers. Unliked Pfizer and Moderna’s mRNA vaccines, CureVac has reported that their vaccine is stable at refrigeration temperatures of 41 degrees.¹

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Novavax

Novavax, a Maryland based company, is developing NVX-CoV2373. Novavax creates vaccines by sticking proteins onto microscopic particles, which they have previously done for an influenza virus that completed Phase 3 clinical trials in March.¹ A Phase 2 trial in South Africa of 2,9000 people is currently underway as well as a Phase 3 clinical trial of 15,000 people in the United Kingdom. Results from both studies are expected in early 2021.¹ On December 28. 2020, a Phase 3, 30,000-person trial began in the United States and Mexico.^1,34 The trial, PREVENT-19, will assess the safety efficacy, and immunogenicity of NVX.CoV2373.³⁴ The trial will be a randomized, placebo controlled, observer-blinded study of persons aged 18 years or older. Of the total participants, 2/3 will receive the vaccine, administered 21 days apart and the other 1/3 will receive placebo.³⁴

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Anhui Zhifei Longcom

A partnership between the Chinese company Anhui Zhifei Longcom and the Chinese Academy of Medical Sciences was created to develop ZF2001.¹ This COVID-19 vaccine contains an adjuvant and a spike protein.¹ A Phase 3 trial of 29,000 people began in December.

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Institute of Medical Biology and the Chinese Academy of Medical Sciences

In May 2020, a Phase 1 trial of 192 participants demonstrated the vaccine as safe and able to produce an immune response.¹ Following data from the Phase 2 trial, the vaccine was determined as most efficacious when administered as a 2 dose series, 14 days apart.¹ In December 2020, a Phase 2 trial of 34,020 participants began, taking place in Brazil and Malaysia.¹ Data are pending. 

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Zydus

ZyCov-D, manufactured by the Indian company Zydus Cadila, is a unique COVID-19 vaccination as it is designed for administration via topical patch.¹ Research began in July 2020; Phase 2 trials began in August 2020 and were completed in December 2020.¹ On January 3, 2021, Zydus Cadila announce the beginning of a Phase 3 trial comprised of 30,000 volunteers. The company plans for distribution of the vaccine by March 2021, should data from the Phase 3 trial support vaccine safety and efficacy.¹

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Research Institute for Biological Safety Problems

Developed by Kazakhstan, research on the QazCovid vaccine began in the summer of 2020.¹ A Phase 1 trial initiated on August 28, 2020, and reports of a completed Phase 2 trial were announced on December 19, 2020. Phase 2 data showed the vaccine as both safe and efficacious, but the exact efficacy rates are not available.¹ A phase 2 trial began at the end of December 2020 and researchers expect results by March 2021.¹

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Vaccines in Phase 2/3 Clinical Trials

Medicago

CoVLP is a plant-based COVID-19 vaccine that is combined with an adjuvant to boost the immune response.¹ Medicago, a Canadian company, received partial funding from Philip Morris, the cigarette maker because they grow vaccines within a wild plant related to tobacco.¹ The company places virus genes in the leaves and uses the plant cells to mimic viruses via plant protein shells.¹ Phase 1 trials demonstrated that, when combined with an adjuvant from GSK, an adequate immune response was reached. A phase 2/3 trial began mid-November 2020.¹ 

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VACCINE DISTRIBUTION

Pfizer-BioNTech

The company has developed a “just-in-time system”, which ships the frozen vaccine vials directly to the location of vaccination.³⁵ Pfizer is working with the Center for Disease Control (CDC) and Operation Warp Speed to prepare for vaccine distribution. The company plans to initiate an Immunization Pilot Program in four states – Rhode Island, Texas, New Mexico, and Tennessee – to determine logistics for delivery and deployment of the vaccine.³⁶ The states were selected based on their varying urban and rural settings as well as their overall differences in size, popularity diversity, and immunization infrastructure.³⁶

The main distribution site in the United States will be out of Kalamazoo, Michigan, with the additional use of the existing distribution center in Pleasant Prairie, Wisconsin.³⁵ The vaccine will be distributed by road and air with the expectation of delivery within a day or two.³⁵

The “just-in-time system” involves specific packaging and storage innovation required to maintain temperatures needed by the vaccine. The thermal shippers, packed with dry ice, are designed to keep the vaccine at temperatures of -70° Celsius (plus or minus 10 degrees) for up to 10 days.³⁵ Each vaccine shipment will be equipped with GPS-enabled thermal sensors that communicate temperature and location with a control tower in order to proactively identify temperature deviations.³⁵ Once the thermal shipper is received at the site of utilization there are 3 options for storage: (1) ultra-low temperature freezers in which the vaccine can be stored for up to six months; (2) the thermal shippers the vaccine was received in. As long as the dry ice is replaced every 5 days, the vaccines can be stored in the shipper for 30 days; and (3) refrigeration units that reach temperatures of 2° to 8° Celsius in which the vaccine can be stored for 5 days.³⁵ The vaccines can remain in the thermal shippers for 30 days and then be moved to a refrigerator (2° to 8° Celsius) for an additional 5 days.¹ Once thawed, the vaccine cannot be re-frozen.³⁵ 

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Moderna

As of November 16, 2020, Moderna announced stability data for their mRNA vaccine. The vaccine remains stable at temperatures of 2° to 8° Celsius (standard refrigeration temperatures) for up to 30 days.³ The vaccine remains stable at room temperature for 12 hours.³⁷

For shipping and long-term storage, the vaccine is stable at -20° Celsius (standard freezer temperatures) for up to 6 months.³⁷ Utilization of standard freezer temperatures, with shipping processes that are already established, makes the distribution of the Moderna vaccine easier.

Moderna is also working with CDC and Operation Warp Speed, as well as McKesson, for the distribution of the vaccine.³⁷ 

In a news release on January 26, 2021, Moderna reported that the company is on track to deliver 100 million doses of their vaccine to the United States government by the end of the first quarter.³⁸ Moderna plans to have 200 million doses total available by the end of the second quarter and aim to produce 500 to 600 million doses globally for 2021.³⁷ As the company continues to increase manufacturing and hires more staff, they predict the potential for up to 1 billion doses produced in 2021.³⁸

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AstraZeneca

The AstraZeneca vaccine candidate does not have much storage and distribution information currently. Pending stability studies, it is estimated the vaccine with be stored and transported at temperatures of 2° to 8° Celsius.³⁶ Shelf-life data are not yet available.

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VACCINE ALLOCATION

The Advisory Committee on Immunization Practices (ACIP), on December 1, 2020, recommended that health-care personnel and long-term care facility residents be the first persons to receive the COVID-19 vaccination.³⁹ This is Phase 1a in the vaccine allocation plan. On December 20, 2020, the ACIP updated its recommendation to include Phase 1b and Phase 1c. Phase 1b, approximately 49 million people, is comprised of persons aged 75 years and older and frontline (non-healthcare) essential workers, and Phase 1c, about 129 million people, is comprised of persons aged 65 years to 74 years, persons aged 16 years to 64 years with high-risk medical conditions, and essential workers not recommended for vaccination in Phase 1b.³⁹ Phase 2 will include all people aged 16 years or older who do not fall into any previous Phases.³⁹

Initial vaccine rollout has been slower than expected and concern has grown over the 2 dose series required by both FDA approved vaccines. Discussion regarding reducing the doses in the series, increasing the time between doses, administering half doses, or mixing vaccine manufacturers have occurred. On January 4, 2021, the FDA released a statement that, despite these concerns, there is not enough data to appropriately recommend any modifications to the dosing or schedules of the vaccines. ⁴⁰ Participants in the Pfizer-BioNTech trial and Moderna trials who only received one dose were not followed for a long enough period of time to ensure protection following a single vaccine dosage. To date, the vaccine protection duration is still being studied and it is not worth the unnecessary risks of administering modified dosage amounts.⁴⁰ 

A recent study compared the antibody response in persons with and without documented COVID-19 immunity. The individuals (seronegative = 68, seropostive = 41) both received a first dose of a coronavirus vaccine.⁴¹ Titers drawn between 9 to 12 days after immunization demonstrated that individuals without prior coronavirus infection had a lower and more variable immune response.⁴¹ Patients who previously had been infected with COVID-19  had an immune response that developed quicker and to a greater extent.⁴¹ The titers of individuals with previous known infection were 10 to 20 times higher compared to individuals without a history of COVID who received their first vaccine dose and 10 times greater following administration of the second dose in the series.⁴¹ Additional studies will be conducted to determine if these differences in immunogenicity continue over time. These results are in preprint and have not yet been peer reviewed. If this data, and other data, are gathered and continue to support these findings, vaccine allocation could be adjusted. Alloation policy could be adjusted such that individuals who had previously had the COVID-19 virus would only receive 1 dose. This would make vaccine doses more available to others who may struggle to get vaccinated or who require 2 doses.⁴¹ 

Vaccination mandates may increase vaccine uptake with no negative effects on vaccination intent. When compared to free choice, vaccine requirements increased vaccination intent across racial and ethnic groups and across levels of psychological reactance within the 3 experiments as part of this study.⁶⁰

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VACCINE SAFETY

During Phase 3 trials of both the Moderna and Pfizer-BioNTech mRNA vaccines, there were no serious safety issues identified. Both vaccines can cause injection site reactions (pain, redness, and swelling) as well as systemic symptoms such as fever, fatigue, headache, and muscle or joint pain.⁴² The clinical trials for both vaccines, phases 1 through 3, excluded participants who had a history of an allergic reaction to vaccine components with Pfizer-BioNTech additionally excluding persons with a history of any severe allergy to a vaccine.⁴²

Within 24 hours of the rollout of the vaccination program with Moderna in the United Kingdom, there were 2 reports of anaphylaxis. Both incidents occurred within women in the 40s who had known allergies and carried injectable epinephrine. Following the EUA of Pfizers-BioNTech's vaccine in the United States, a 32-year-old woman in Alaska, without any prior allergies, experience an anaphylactic reaction.⁴² Since then, several more cases of anaphylaxis following vaccination with the Pfizer-BioNTech vaccine have occurred. It is too soon to have data regarding the incidence of anaphylaxis with the Moderna vaccine in the United States. CDC has since recommended that any person who has a history of allergy to any component of the vaccine should be excluded from receiving the vaccine.⁴² Despite the seriousness of anaphylaxis, the reaction is a rare event. 

Both Pfizer-BioNTech and Moderna utilize mRNA technology for their vaccines. Despite the technology of mRNA vaccines not being new, these two vaccines are the first ones to have been issued a EUA. There are still not any mRNA vaccines that are licensed by the FDA. Due to this, there is no prior experience with allergic reactions associated with mRNA vaccines within a real-life setting.⁴² Further data is required to determine if the allergic reactions are caused by the mRNA component or by the lipid component of the vaccine. 

On January 22, 2021, CDC released their Morbidity and Mortality Weekly Report (MMWR) regarding anaphylaxis in patients receiving their first dose of the Moderna vaccine. Between December 21, 2020 and January 10, 2021, there were 10 cases of anaphylaxis detected by the Vaccine Adverse Event Reporting System out of a total 4,041,396 first doses administered.⁴³ This equates to 2.5 cases of anaphylaxis per 1 million doses administered. These results are comparable to other vaccines; a previous analysis of the Pfizer-BioNTech COVID-19 vaccine had an estimated rate of 11.1 cases per 1 million doses administered.⁴⁴ In 9 out of ten cases, the onset of the reaction occurred within 15 minutes of administration.⁴³ All cases of anaphylaxis occurred in women.⁴³ This is only a short period of time for data collection continued monitoring will be necessary to determine rates of anaphylaxis as time progresses. 

In May of 2021, an exploratory cohort of 103 women indicated that pregnant and lactating women who received a COVID-19 mRNA vaccine had an immunogenic response.⁵⁷ Vaccine-elicited antibodies were found in infant cord blood and breast milk. Both pregnant and non-pregnant vaccinated women developed immunogenicity to SARS-CoV-2 variants.

Vaccination against COVID-19 during pregnancy was not associated with an increased risk of early pregnancy loss, according to the results of a recent case-control study. Of the 13,956 pregnant women from Norway included in the study, 5.5% were vaccinated. Of the 4521 women in the study who had miscarriages within their first trimester, 5.1% were vaccinated. Miscarriage or ongoing pregnancy was observed at 5-week and 3-week windows following vaccination.⁵⁹

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VACCINE DEVELOPMENT DISCONTINUATION

In a news release on January 25, 2021, Merck announced that the company is discontinuing the development of their 2 COVID-19 vaccine candidates, V590 and V591.⁴⁵ Merck plans on shifting the company's focus to the development of their 2 therapeutic candidates, MK-4482 and MK-7110.⁴⁵ While both vaccine candidates were generally well tolerated, results from Phase 1 clinical trials demonstrated decreased efficacy compared to other COVID-19 vaccines.⁴⁵

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COVID-19 VARIANTS

Given the nature of viruses and how they mutate over time, variants of the COVID-19 virus were expected. Within the last several months, multiple variants of the COVID-19 virus have been identified. Three variants have been identified to date - B.1.1.7, B.1.351, and P.1 - and are circulating worldwide.⁴⁶ The Centers for Disease Control and Prevention will continue to conduct SARS-CoV-2 strain surveillance to support public health response.⁴⁷

One of the most concerning consequences of variants is the ability to evade vaccine immunity. For a study conducted in 20 volunteers who received either the Moderna (n = 14) or Pfizer-BioNTech (n = 6) vaccine, researchers analyzed the ability of vaccine-elicited monoclonal antibodies to neutralize the SARS-CoV-2 virus with different variants.⁴⁸ The researchers found that variants with the K417N/T, E484K, and N501Y mutations can reduce the neutralization ability of vaccines.⁴⁸ The researchers recommended that COVID-19 vaccines may need to be updated and immunity should be monitored to track and account for viral evolution.⁴⁸

Moderna announced on January 25, 2021, that in vitro neutralization studies have shown that individuals who have received the Moderna COVID-19 vaccine still have neutralizing activity against the new COVID-19 variants.⁴⁹ Vaccination with the Moderna vaccine produced neutralizing titers against all emerging variants tests. There was no significant impact on the the B.1.1.7 variant but there was a six-fold reduction in neutralizing titers in the B.1.351 variant.⁴⁹ However, the titer levels were still above the threshold required to be considered protective.⁴⁹ 

Interim results from a phase III clinical trial of the Novavax vaccine demonstrate that it is 95.6% effective against the original SARS-CoV-2 virus, 85.6% effective against the B.1.1.7 variant, and 60% effective against the B.1.351 variant.⁵⁰ The data was gathered from 15,000 participants in the United Kingdom. Of the patients who contracted symptomatic COVID-19 (n = 62), fifty six of the individuals were in the placebo group.⁴⁹ Only 1 individual, who was in the placebo group, was diagnosed with severe coronavirus.⁵⁰ Of the 62 individuals with COVID, 32 of them were diagnosed with the UK B.1.1.7 variant.⁵⁰

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CDC VACCINE SCHEDULE RECOMMENDATIONS 

CDC released their updated vaccine schedule recommendations for 2021 on February 11, 2021.⁵¹ The adult vaccine immunization schedule (ages 19 years and older), developed by the ACIP, recommends the use of COVID-19 vaccines under the guidance of the  EUAs for each specific vaccine.⁵¹ The Advisory Committee on Immunization Practices (ACIP) also recommends COVID-19 vaccine usage in children and adolescents, however, individuals must be 16 years of age or older to receive the Pfizer-BioNTech vaccine and 18 years of age or older to receive the Moderna vaccine.⁵¹ 

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BREAKTHROUGH CASES

CDC is continuing to monitor the frequency of symptomatic and non-symptomatic breakthrough cases among fully vaccinated individuals in the US. As of July 19, 2021, among the >161 million fully vaccinated individuals in the US, a total of 5914 breakthrough cases were reported. Of these, 2881 were female (49%), 4392 were 65 years of age or older (74%), 1164 (20%) were asymptomatic, 5601 (95%) required hospitalizations, of which 1529 cases (27%) were reported as asymptomatic or not related to COVID-19), and 1141 deaths occurred, of which 292 (26%) were reported as asymptomatic or not related to COVID-19.⁵⁸

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BOOSTER DOSES

The Centers for Disease Control and Prevention's Advisory Committee has updated their interim recommendations on additional primary and booster doses. An additional primary vaccine dose is now recommended for moderately to severely immunocompromised individuals 28 days or more following administration of their second primary series dose. Individuals must be aged 12 years or older to receive an additional primary dose of the Pfizer-BioNTech vaccine, and individuals must be aged 18 years or older to receive an additional dose of the Moderna vaccine.

Booster doses are now recommended in certain patient populations. For those who received an mRNA vaccine, booster doses should be administered 6 months or longer following completion of the primary vaccine series. For those who received the Janssen vaccine, booster doses should be administered 2 months or longer after primary vaccination. Among the patient populations included are individuals aged 65 years or older, individuals aged 18 years or older who live in a long-term care setting, individuals aged 18 to 64 years with certain underlying conditions, and individuals aged 18 to 64 years who are at high-risk of exposure due to their occupation or institution.⁶³

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REFERENCES

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