Author: Susan J. Blalock

Categories
COVID-19 Vaccine Janssen Johnson & Johnson Safety monitoring

Johnson & Johnson (Janssen) Vaccine: April 2021

Bottom Line About Rare Blood Clots With Johnson & Johnson (Janssen) COVID-19 Vaccine

    • The Johnson & Johnson (Janssen) COVID-19 vaccine appears to increase the risk of developing rare blood clots, combined with low platelet counts. The medical term for this condition is Thrombosis with Thrombocytopenia Syndrome (TTS).
    • As of April 12, 2021, nearly 7 million people had received this vaccine in the United States.
    • As of April 21, 2021, 15 people who had received the vaccine developed TTS and 3 of these people died.
    • The risk of developing TTS following vaccination is very low. For every 1 million women between 18 and 49 years old, about 7 developed TTS. The risk is even lower among older women and men of any age.
    •  Analyses performed by scientists at the Center for Disease Control and Prevention (CDC) estimated that the risk of dying of COVID-19 is greater than the risk of developing TTS after receiving the Johnson & Johnson (Janssen) vaccine. Therefore, they continue to believe that the benefits of the vaccine outweigh the risks.
    • The small risk of TTS can be avoided by being vaccinated with either the Pfizer/BioNTech or Moderna vaccines. (No cases of TTS have been observed among people who have received the Pfizer/BioNTech or Moderna vaccines. Over 180 million doses of these vaccines have been administered in the US.)
    •  CDC encourages health care providers to talk to women between the ages of 18 and 49 about the risk of TTS with the Johnson & Johnson (Janssen) vaccine and to discuss the possibility of using one of the other approved COVID-19 vaccines instead. However, if a woman is unable to use either of the other vaccines or prefers a vaccine that only requires one shot, both the FDA and CDC considers the Johnson & Johnson (Janssen) vaccine safe and effective to use.
    • CDC continues to emphasize that vaccines save lives and encourages all adults to be vaccinated.

April 13 – April 23, 2021: On April 13th, the US Food and Drug Administration (FDA) recommended a pause in use of the Johnson & Johnson (Janssen) COVID-19 vaccine that received an Emergency Use Authorization in the US on February 27, 2021. As of April 12, 2021, more than 6.8 million doses of this vaccine had been administered. The pause was recommended in response to 6 cases of a rare type of blood clot (cerebral venous sinus thrombosis, CVST) combined with low platelet counts. The medical term for this condition is Thrombosis with Thrombocytopenia Syndrome (TTS). All six cases occurred in women between 18 and 48 years old within two weeks following vaccination with the Johnson & Johnson (Janssen) vaccine.

A drug called heparin is usually used to treat blood clots. However, heparin can make TTS worse. The purpose of the pause was 2-fold. First, it allowed time for the FDA and Centers for Disease Control and Prevention (CDC) to make both patients and health care providers aware of this condition, including symptoms of a possible clot, the importance of early diagnosis and treatment, and treatments to implement (and those to avoid).

Currently, CDC recommends that people who receive the Johnson & Johnson (Janssen) vaccine, should be on the lookout for the following symptoms of a possible clot for three weeks after receiving the vaccine and should seek medical care right away if they develop any of these symptoms. The symptoms to watch for include: severe or persistent headaches or blurred vision, shortness of breath, chest pain, leg swelling, persistent abdominal pain, and easy bruising or tiny blood spots under the skin beyond the injection site

The second reason for the pause is that it gave the FDA and CDC time to review the cases that had been identified and determine the best way to proceed. Since April 13th, two emergency meetings of CDC’s Advisory Committee on Immunization Practices (ACIP) have been held. Both of these meetings were open to the public and live-streamed. Links to materials from these meetings are provided below.

At the end of the meeting on April 23rd, the Committee recommended that use of the Johnson & Johnson (Janssen) vaccine resume in the United States without any age or sex restrictions. This recommendation was based on data concerning the risks and benefits associated with different vaccination strategies (e.g., limiting use of the vaccine to older adults), as well as the feasibility of implementing different strategies on a nationwide basis in the midst of the current global pandemic.

TTS is a very rare condition, affecting only 0.7 to 1.6 people per million in the US each year. Although the mechanism of action is not clear, it is likely that the Johnson & Johnson (Janssen) vaccine increases the risk of developing TTS. However, the likelihood of developing TTS following vaccination is very small.

As of April 21, 2021, a total of 15 cases of TTS had been confirmed among the nearly 8 million people who had received the Johnson & Johnson (Janssen) vaccine. All of these cases occurred within about two weeks following vaccination. As of April 21st, 3 of the 15 people who developed TTS following vaccination had died and 4 remained hospitalized in an intensive care unit. (For comparison, no cases of TTS have been reported following the administration of the Pfizer/BioNTech or Moderna vaccines. As of April 21st, over 180 million doses of these vaccines had been administered in the US.)

As shown in the table below, most of the 15 cases of TTS occurred among women between the ages of 18 and 49. In this group, 7.0 cases of TTS were reported for every 1 million doses of the Johnson & Johnson (Janssen) vaccine administered. Thus, even in this group, the likelihood of developing TTS following vaccination is very small.

Given this serious (but rare) risk, the question becomes whether the benefits associated with the Johnson & Johnson (Janssen) vaccine outweigh the risks. From a public health perspective, the answer is pretty clear. As shown in the table below, CDC scientists estimated that continuing to use the Johnson & Johnson (Janssen) vaccine for adults age 18 years and older would prevent 586 to 1,435 deaths due to COVID-19, while causing only 26 cases of TTS. The deaths prevented are the result of being able to vaccinate all interested adults more quickly than if only the Pfizer/BioNTech and Moderna vaccines were available.

CDC scientists also examined vaccine risks/benefits separately for younger women, older women, younger men, and older men. These analyses assumed that the people did not receive one of the other COVID-19 vaccines available in the US. As shown in the table below, the benefit/risk ratio was smallest for women in the younger age group.

At the end of the meeting on April 23rd, the Committee recommended that use of the Johnson & Johnson (Janssen) vaccine resume in the US without any age or sex restrictions. However, it was understood that the FDA would add a warning statement about the risk of TTS in materials distributed to patients and health care providers. In addition, CDC recommends that for females under the age of 50 health care providers discuss the option of receiving either the Pfizer/BioNTech vaccine or the Moderna vaccine instead of the Johnson & Johnson vaccine. They also emphasized that the risk of TTS is very low and that it is important for all individuals to be vaccinated. For individuals who are unable to receive one of the other vaccines or who cannot complete the 2-dose series required for both the Pfizer/BioNTech and Moderna vaccines, experts believe that the potential benefits of the Johnson & Johnson (Janssen) vaccine outweigh the known and potential risks.

In conclusion, the ability of FDA and CDC scientists to quickly identify the very rare risk of TTS should reassure the public that surveillance systems such as the Vaccine Adverse Event Reporting System (VAERS) are working the way they should. Very rare adverse events are almost impossible to discover in clinical trials because they may not occur in even large trials involving tens of thousands of people. Once the possible risk of TTS was identified, the FDA and CDC worked together to implement a pause in use of the Johnson & Johnson (Janssen) vaccine, educate the public and health care providers about the potential risk of TTS, and implement an emergency review process by independent scientists before moving forward. This review process was transparent. Committee meetings were open to the public and all meeting materials remain available online. We applaud the FDA and CDC for their work to review the evidence and chart a course forward that is likely to prevent thousands of deaths over the coming months.

Other References:

Slides used in the scientific presentations made during the meeting on April 14th can be found here. The meeting can be viewed in full using the following links: Welcome & Coronavirus Disease 2019 (COVID-19) Vaccines and Public Comment & Vote. 

Slides used in the scientific presentations made during the meeting on April 23rd can be found here. It can be viewed in full using the following links: Welcome & Coronavirus Disease 2019 (COVID-19) Vaccines, Public Comment , and Janssen COVID-19 vaccine. 

The revised Fact Sheet for Healthcare Providers Administering Vaccine can be obtained here. This fact sheet now includes a warning about TTS.

A fact sheet for patients prepared by CDC can be found here.

A paper published in Morbidity and Mortality Weekly Report (MMRW) discussing the risk of TTS following administration of the Johnson & Johnson (Janssen) vaccine can be found here.

Categories
Janssen Johnson & Johnson

Janssen (Johnson & Johnson) Vaccine

This page summarizes findings from the Phase 3 study, ENSEMBLE, testing the efficacy and safety of the Janssen (Johnson & Johnson) COVID-19 vaccine, Ad26.COV2.S (also known as JNJ-78436735). This is a non-replicating viral vector vaccine. Over 40,000 people (age 18 years and older) participated in the study. Half of them received a single dose of the Ad26.COV2.S vaccine, while the other half received a placebo vaccine. A brief summary of the design of this study can be found in Table 1 on this website. More detailed information about the design of the study can be found on ClinicalTrials.Gov and the full protocol for the study can be found here.

Most of the data summarized on this page are from analyses Janssen and the US Food and Drug Administration (FDA) conducted in February 2021. The primary efficacy analyses were limited to data collected before January 22, 2021. A total of 39,321 study participants who had no evidence of a previous SARS-CoV-2 infection were included in the primary analyses examining vaccine efficacy. As of January 22, 2021, these participants had been followed an average of 2 months following vaccination. The safety analyses included an additional 4,462 people who had evidence of a previous SARS-CoV-2 infection, bringing the total number of people included in the safety analyses up to 43,783. The study is continuing and the findings may change somewhat as more data are collected. At the bottom of this page, we provide links to more detailed information reporting study findings prepared by Janssen, the FDA, and the Centers for Disease Control and Prevention (CDC).

The table below show characteristics of study participants. These characteristics did not differ between people who received the Ad26.COV2.S vaccine and those who received the placebo vaccine.

Participant Characteristic (N=43,783) # (%)
Age group
18-65 35,222 (80.4%)
≥66 8,561 (19.6%)
Female 19,722 (45.0%)
Race
White 25,696 (58.7%)
Black or African American 8,515 (19.4%)
American Indian or Alaska Native 4,143 (9.5%)
Multiple 2,449 (5.6%)
Other or Unknown 2,980 (6.8%)
Hispanic 19,837 (45.3%)
Region
United States 19,302 (44.1%)
Latin America 17,905 (40.9%)
South Africa 6,576 (15.0%)
Had at least one chronic health problem at start of study 17,858 (40.8%)

 

Vaccine Efficacy

The figure below shows when the cases of COVID-19 occurred in the groups that received the placebo vaccine (brown line) and the Ad26.COV2.S vaccine (blue line). This figure is from the Briefing Document prepared by the FDA for the advisory committee meeting on February 26, 2021. The figure suggests that the Ad26.COV2.S vaccine starts to provide protection around 2 to 3 weeks following administration and continues to provide protection for at least 2 to 3 months. As participants in the study are followed longer, this type of figure will give us an idea of the extent to which vaccine efficacy may decrease over time. (You can click on the figure to enlarge it.)

Vaccine Safety

To assess vaccine safety, a subset of 6,376 participants completed an electronic diary each day for seven days after receiving either the placebo or Ad26.COV2.S vaccine. The diary included a list of possible vaccine side effects. Participants were asked to check any side effects they were having that day and to provide information about the severity of the side effect. The list included both local (e.g., pain at the injection site) and systemic side effects (e.g., fever). Information reported in these diaries is presented in the figures below.

Local Side Effects: Any Severity

The figure below shows the percentage of participants who had local side effects of any severity. On average, these side effects started within two days of the the injection and lasted 2 to 3 days. Participants age 60 and older were somewhat less likely to report local side effects than younger participants. 

Local Side Effects: Severe

A side effect was considered severe if it prevented a participant from performing his/her usual daily activities (including social activities) or required medical care. A total of 29 people experienced at least one severe local side effect; 23 (0.7%) people who received the Ad26.COV2.S vaccine and 6 (0.2%) people who received the placebo vaccine. None of the study participants had a local side effect that caused them to visit the emergency room or required hospitalization.

Systemic Side Effects: Any Severity

The figure below shows the percentage of participants who had systemic side effects of any severity.  Most of these side effects started within two days of the the injection and lasted 1 to 2 days. All of the systemic side effects were reported less often by participants age 60 and older than younger participants.

Systemic Side Effects: Severe

As described above, a side effect was considered severe if it prevented a participant from performing his/her usual daily activities (including social activities) or required medical care. A total of 82 people experienced at least one severe systemic side effect; 61 (1.8%) people who received the Ad26.COV2.S vaccine and 21 (0.6%) people who received the placebo vaccine. None of the study participants had a systemic side effect that caused them to visit the emergency room or required hospitalization.

Other Potential Side Effects

All 43,783 study participants are being followed for two years to determine if they experience any serious adverse events following vaccination. The safety findings summarized below are based on data collected before January 22, 2021. At that time, participants had been followed for an average of 2 months following vaccination.

  • 153 participants (91 in the Ad26.COV2.S group and 62 in the placebo group) reported joint pain following vaccination. The FDA concluded that these events were probably caused by vaccine reactogencity (the immune response the vaccine is designed to stimulate).
  • 50 participants (31 in the Ad26.COV2.S group and 18 in the placebo group) reported muscle weakness following vaccination. The FDA concluded that these events were probably caused by vaccine reactogencity (the immune response the vaccine is designed to stimulate). 
  • 24 participants (14 in the Ad26.COV2.S group and 10 in the placebo group) experienced a thromboembolic event; most involved either a deep vein thrombosis or pulmonary embolism. Many of these participants had health conditions that increased their risk of having a thromboembolic event, making if difficult to determine any role the vaccine may have played. After reviewing all of the individual cases, the FDA concluded that they could not rule out the possibility that the Ad26.COV2.S vaccine may have been a contributing factor. They recommended continued surveillance of thromboembolic events as the vaccine is used in more people.
  • 6 participants (all in the Ad26.COV2.S group) developed tinnitis (ringing in the ears) after receiving the vaccine. All of these participants had health conditions that increased their risk of tinnitis. After reviewing all of the individual cases, the FDA concluded that they could not determine whether the vaccine had been a contributing factor.
  • 6 participants (5 in the Ad26.COV2.S group and 1 in the placebo group) experienced urticaria (a rash with intense itching) within 7 days following vaccination. All 6 cases were considered non-serious. However, one person in the Ad26.COV2.S group also reported a hypersensitivity reaction that was rated as serious. This participant experienced lip swelling that began four days after vaccination. The FDA concluded that the Ad26.COV2.S vaccine likely caused these adverse events.
  • 5 participants (4 in the AD26.COV2.S group and 1 in the placebo group) experienced a seizure following vaccination. After reviewing all of the individual cases, the FDA concluded that they could not determine whether the vaccine had been a contributing factor.
  • 1 person experienced severe pain in the arm where the Ad26.COV2.S vaccine was administered. The pain began at the time of vaccination, was ongoing 10 weeks following vaccination, and did not respond to pain medication. The FDA considered this a serious adverse event likely related to the vaccine.

Questions That Remain

Unknown Benefits/Data Gaps

  • Duration of protection. Currently, only about 1,000 study participants have been followed more than 90 days after receiving the Ad26.COV2.S vaccine. Therefore, at this point in time, it is not possible to determine how long protection from COVID-19 is likely to last.
  • Vaccine effectiveness against asymptomatic infection and transmission. More data are needed to determine if the Ad26.COV2.S vaccine helps prevent asymptomatic COVID-19 and virus shedding and transmission, particularly among people with asymptomatic infections.
  • Vaccine effectiveness against mortality and long-term health effects of COVID-19. It is reasonable to expect that the Ad26.COV2.S vaccine will reduce the risk of dying from COVID-19 or experiencing long-term health problems (e.g., organ damage) as a result of the disease. However, more data are needed to confirm these potential benefits. It is likely that answers to these questions will come from observational studies involving millions of people. People in observational studies are not randomized to receive a particular type of treatment. Therefore, no one would be required to get the Ad26.COV2.S vaccine and no one would be denied the vaccine. Nonetheless, researchers can use data from observational studies to see if there are differences in health outcomes (e.g., death, hospitalization) between people who received a certain type of treatment (for example, the Ad26.COV2.S vaccine) and those who did not.
  • Effectiveness in specific population subgroups: Currently, not enough data are available to assess vaccine efficacy in certain population subgroups such as people who are immunocompromised, including those with HIV/AIDS.
  • Effectiveness of the vaccine going forward: As the SARS-CoV-2 virus continues to evolve, it is not clear that the vaccine will retain a high level of efficacy against emerging variants. Janssen plans to conduct large observational studies using health insurance claims and electronic health records to estimate vaccine effectiveness as it is made available to millions of people in the general public over the coming months.

Unknown Risks/Data Gaps

  • Pregnancy and Lactation: The Phase 3 trial excluded women who were pregnant or breastfeeding at the start of the trial and female participants of child-bearing potential agreed to practice adequate conception for 3 months following vaccination. Most clinical trials of investigational drugs do not include pregnant women, so this is not unusual. If you would like more information about the inclusion of pregnant women in clinical trials, see this FDA Guidance document.

In spite of the exclusion of pregnant women from the Phase 3 trial, 8 study participants (4 in the Ad26.COV2.S group and 4 in the placebo group) have reporting pregnancies since receiving the vaccine/placebo. As of January 22, 2021, one woman in the Ad26.COV2.S group reported a miscarriage and another reported an ectopic pregnancy. In the placebo group, one woman reported a miscarriage and two women reported elective abortions. The FDA concluded that not enough data were available to make conclusions about the safety of the vaccine in pregnant and lactating women and their babies. However, they noted that a study conducted in animals  found no evidence of harmful effects on reproduction, fetal development, or development after birth.

The FDA advises women who are pregnant or breastfeeding to discuss their options for vaccination with their healthcare provider.

Why might a woman who is pregnant consider getting the Ad26.COV2.S vaccine? First, among women with COVID-19, research suggests that pregnancy may increase the risk of severe disease. (See these two reports from CDC for more information 1, 2.) Second, among pregnant women, getting COVID-19 may increase the risk of preterm birth. Being vaccinated against COVID-19 may lower these risks. Finally, certain medical conditions increase the risk of developing severe COVID-19. Therefore, it is especially important for women with any of these conditions to discuss their options for vaccination with their healthcare provider.​

The information in the box below is taken directly from the FDA-approved Fact Sheet for Healthcare Providers (pages 15-16) dated 2/27/2021

11.1 Pregnancy

Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to
Janssen COVID-19 Vaccine during pregnancy. Women who are vaccinated with Janssen COVID19 Vaccine during pregnancy are encouraged to enroll in the registry by visiting https://cviper.
pregistry.com.

Risk Summary
All Pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically
recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Available data on Janssen COVID-19 Vaccine administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.

In a reproductive developmental toxicity study female rabbits were administered 1 mL of the
Janssen COVID-19 Vaccine (a single human dose is 0.5 mL) by intramuscular injection 7 days
prior to mating and on Gestation Days 6 and 20 (i.e., one vaccination during early and late
gestation, respectively). No vaccine related adverse effects on female fertility, embryo-fetal or postnatal development up to Postnatal Day 28 were observed.

11.2 Lactation

Risk Summary
Data are not available to assess the effects of Janssen COVID-19 Vaccine on the breastfed infant or on milk production/excretion.
  • Adverse reactions that are very uncommon or that require longer follow-up to detect. In the Phase 3 trial, about 20,000 people received the Ad26.COV2.S vaccine. This may not be enough to discover uncommon (and potentially serious) side effects. In addition, when the FDA issued the emergency use authorization (EUA) for the Ad26.COV2.S vaccine in February 2021, study participants had only been followed for an average of 8 weeks. The FDA considered this an adequate length of follow-up for the purpose of issuing the EUA because historical data indicate that most adverse events from vaccines occur within 6 weeks following vaccination. Nonetheless, surveillance systems (including, the Vaccine Adverse Event Reporting System, VAERS, and v-safe) are in place to detect uncommon or delayed adverse events as soon as possible under the EUA.
  • Vaccine-enhanced disease. Data from the Phase 3 trial suggest that the Ad26.COV2.S vaccine helps protect against severe COVID-19. However, it is still unknown if the risk of more severe disease following vaccination may increase over time, especially if immunity decreases over time. Study participants continue to be followed to assess this potential risk.
  • Individuals who are immunocompromised. The FDA concluded that there is not enough information to draw conclusions about the safety and efficacy of the Ad26.COV2.S vaccine in individuals who are immunocompromised. Individuals who are immunocompromised or on a medication that affects the immune system are advised to talk to their health care provider. More information about vaccination decisions for people with underlying medical conditions is available from the CDC.

Other Resources

  • 119-page report and an 8-page addendum to the report prepared by Janssen (Johnson & Johnson) when requesting an emergency use authorization for the Ad26.COV2.S vaccine
  • 62-page briefing document prepared by the FDA after reviewing the materials submitted by Janssen
  • Fact Sheets for (1) Healthcare Providers Administering Vaccine and (2) Recipients and Caregivers can be downloaded in multiple languages from the Janssen website

 

Categories
Janssen Johnson & Johnson

Johnson & Johnson (Janssen) COVID-19 Vaccine Updates

Summary of findings from Phase 3 trial evaluating the Janssen (Johnson & Johnson) COVID-19 vaccine is available here. Data from this study were analyzed by the US Food and Drug Administration (FDA) before it issued an emergency use authorization for this vaccine.

 

Bottom Line About Rare Blood Clots With Johnson & Johnson (Janssen) COVID-19 Vaccine

    • The Johnson & Johnson (Janssen) COVID-19 vaccine appears to increase the risk of developing rare blood clots, combined with low platelet counts. The medical term for this condition is Thrombosis with Thrombocytopenia Syndrome (TTS). 
    • As of April 12, 2021, nearly 7 million people had received this vaccine in the United States.
    • As of April 21, 2021, 15 people who had received the vaccine developed TTS and 3 of these people died. 
    • The risk of developing TTS following vaccination is very low. For every 1 million women between 18 and 49 years old, about 7 developed TTS. The risk is even lower among older women and men of any age. 
    •  Analyses performed by scientists at the Center for Disease Control and Prevention (CDC) estimated that the risk of dying of COVID-19 is greater than the risk of developing TTS after receiving the Johnson & Johnson (Janssen) vaccine. Therefore, they continue to believe that the benefits of the vaccine outweigh the risks.
    • The small risk of TTS can be avoided by being vaccinated with either the Pfizer/BioNTech or Moderna vaccines. (No cases of TTS have been observed among people who have received the Pfizer/BioNTech or Moderna vaccines. Over 180 million doses of these vaccines have been administered in the US.)
    •  CDC encourages health care providers to talk to women between the ages of 18 and 49 about the risk of TTS with the Johnson & Johnson (Janssen) vaccine and to discuss the possibility of using one of the other approved COVID-19 vaccines instead. However, if a woman is unable to use either of the other vaccines or prefers a vaccine that only requires one shot, both the FDA and CDC considers the Johnson & Johnson (Janssen) vaccine safe and effective to use.
    • CDC continues to emphasize that vaccines save lives and encourages all adults to be vaccinated.

April 13 – April 23, 2021: On April 13th, the US Food and Drug Administration (FDA) recommended a pause in use of the Johnson & Johnson (Janssen) COVID-19 vaccine that received an Emergency Use Authorization in the US on February 27, 2021. As of April 12, 2021, more than 6.8 million doses of this vaccine had been administered. The pause was recommended in response to 6 cases of a rare type of blood clot (cerebral venous sinus thrombosis, CVST) combined with low platelet counts. The medical term for this condition is Thrombosis with Thrombocytopenia Syndrome (TTS). All six cases occurred in women between 18 and 48 years old within two weeks following vaccination with the Johnson & Johnson (Janssen) vaccine. 

A drug called heparin is usually used to treat blood clots. However, heparin can make TTS worse. The purpose of the pause was 2-fold. First, it allowed time for the FDA and Centers for Disease Control and Prevention (CDC) to make both patients and health care providers aware of this condition, including symptoms of a possible clot, the importance of early diagnosis and treatment, and treatments to implement (and those to avoid).

Currently, CDC recommends that people who receive the Johnson & Johnson (Janssen) vaccine, should be on the lookout for the following symptoms of a possible clot for three weeks after receiving the vaccine and should seek medical care right away if they develop any of these symptoms. The symptoms to watch for include: severe or persistent headaches or blurred vision, shortness of breath, chest pain, leg swelling, persistent abdominal pain, and easy bruising or tiny blood spots under the skin beyond the injection site

The second reason for the pause is that it gave the FDA and CDC time to review the cases that had been identified and determine the best way to proceed. Since April 13th, two emergency meetings of CDC’s Advisory Committee on Immunization Practices (ACIP) have been held. Both of these meetings were open to the public and live-streamed. Links to materials from these meetings are provided below. 

At the end of the meeting on April 23rd, the Committee recommended that use of the Johnson & Johnson (Janssen) vaccine resume in the United States without any age or sex restrictions. This recommendation was based on data concerning the risks and benefits associated with different vaccination strategies (e.g., limiting use of the vaccine to older adults), as well as the feasibility of implementing different strategies on a nationwide basis in the midst of the current global pandemic.

TTS is a very rare condition, affecting only 0.7 to 1.6 people per million in the US each year. Although the mechanism of action is not clear, it is likely that the Johnson & Johnson (Janssen) vaccine increases the risk of developing TTS. However, the likelihood of developing TTS following vaccination is very small. 

As of April 21, 2021, a total of 15 cases of TTS had been confirmed among the nearly 8 million people who had received the Johnson & Johnson (Janssen) vaccine. All of these cases occurred within about two weeks following vaccination. As of April 21st, 3 of the 15 people who developed TTS following vaccination had died and 4 remained hospitalized in an intensive care unit. (For comparison, no cases of TTS have been reported following the administration of the Pfizer/BioNTech or Moderna vaccines. As of April 21st, over 180 million doses of these vaccines had been administered in the US.) 

As shown in the table below, most of the 15 cases of TTS occurred among women between the ages of 18 and 49. In this group, 7.0 cases of TTS were reported for every 1 million doses of the Johnson & Johnson (Janssen) vaccine administered. Thus, even in this group, the likelihood of developing TTS following vaccination is very small.

 

Given this serious (but rare) risk, the question becomes whether the benefits associated with the Johnson & Johnson (Janssen) vaccine outweigh the risks. From a public health perspective, the answer is pretty clear. As shown in the table below, CDC scientists estimated that continuing to use the Johnson & Johnson (Janssen) vaccine for adults age 18 years and older would prevent 586 to 1,435 deaths due to COVID-19, while causing only 26 cases of TTS. The deaths prevented are the result of being able to vaccinate all interested adults more quickly than if only the Pfizer/BioNTech and Moderna vaccines were available.

CDC scientists also examined vaccine risks/benefits separately for younger women, older women, younger men, and older men. These analyses assumed that the people did not receive one of the other COVID-19 vaccines available in the US. As shown in the table below, the benefit/risk ratio was smallest for women in the younger age group.

At the end of the meeting on April 23rd, the Committee recommended that use of the Johnson & Johnson (Janssen) vaccine resume in the US without any age or sex restrictions. However, it was understood that the FDA would add a warning statement about the risk of TTS in materials distributed to patients and health care providers. In addition, CDC recommends that for females under the age of 50 health care providers discuss the option of receiving either the Pfizer/BioNTech vaccine or the Moderna vaccine instead of the Johnson & Johnson vaccine. They also emphasized that the risk of TTS is very low and that it is important for all individuals to be vaccinated. For individuals who are unable to receive one of the other vaccines or who cannot complete the 2-dose series required for both the Pfizer/BioNTech and Moderna vaccines, experts believe that the potential benefits of the Johnson & Johnson (Janssen) vaccine outweigh the known and potential risks. 

In conclusion, the ability of FDA and CDC scientists to quickly identify the very rare risk of TTS should reassure the public that surveillance systems such as the Vaccine Adverse Event Reporting System (VAERS) are working the way they should. Very rare adverse events are almost impossible to discover in clinical trials because they may not occur in even large trials involving tens of thousands of people. Once the possible risk of TTS was identified, the FDA and CDC worked together to implement a pause in use of the Johnson & Johnson (Janssen) vaccine, educate the public and health care providers about the potential risk of TTS, and implement an emergency review process by independent scientists before moving forward. This review process was transparent. Committee meetings were open to the public and all meeting materials remain available online. We applaud the FDA and CDC for their work to review the evidence and chart a course forward that is likely to prevent thousands of deaths over the coming months.

Other References:

Slides used in the scientific presentations made during the meeting on April 14th can be found here. The meeting can be viewed in full using the following links: Welcome & Coronavirus Disease 2019 (COVID-19) Vaccines and Public Comment & Vote. 

Slides used in the scientific presentations made during the meeting on April 23rd can be found here. It can be viewed in full using the following links: Welcome & Coronavirus Disease 2019 (COVID-19) Vaccines, Public Comment , and Janssen COVID-19 vaccine. 

The revised Fact Sheet for Healthcare Providers Administering Vaccine can be obtained here. This fact sheet now includes a warning about TTS.

A fact sheet for patients prepared by CDC can be found here.

A paper published in Morbidity and Mortality Weekly Report (MMRW) discussing the risk of TTS following administration of the Johnson & Johnson (Janssen) vaccine can be found here.

February 26, 2021: The Food and Drug Administration (FDA) Vaccines and Related Biological Products Advisory Committee (VRBPAC) recommended approval of an Emergency Use Authorization for the Janssen COVID-19 vaccine by a vote of 22-0 with no abstentions. Following the meeting, the FDA announced that it “has informed the sponsor that it will rapidly work toward finalization and issuance of an emergency use authorization. The agency has also notified our federal partners involved in vaccine allocation and distribution so they can execute their plans for timely vaccine distribution.”

Johnson & Johnson announced that it is able to begin delivery of the Janssen vaccine immediately after the EUA is issued and expects to deliver at least 20 million doses of the vaccine to the US by the end of March. Because this vaccine only requires one shot, that translates into 20 million people being fully vaccinated with the Janssen vaccine by the end of March. The Company plans to deliver a total of 100 million doses of the vaccine to the US by July 1, 2021.  

The Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) will meet on Sunday, February 28th to discuss recommendations concerning utilization and distribution of the Janssen vaccine. On Monday, March 1st, the ACIP will meet to discuss issues concerning COVID-19 vaccines more generally. The full agenda for the meetings on both Sunday and Monday can be found here. The meeting is open to the public and can be viewed via webcast. A link for the webcast can be found here.

February 25, 2021: The U.S. Food and Drug Administration (FDA) will discuss Johnson & Johnson’s (Janssen) request for an emergency use authorization (EUA) for the Company’s vaccine candidate, AD26.COV2.S at a meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) tomorrow (February 26, 2021). The meeting is scheduled to begin a 9:00 am EST. A draft agenda for the meeting can be found here. The meeting is open to the public and will be available to watch via the following links: 

February 24, 2021: The US Food and Drug Administration (FDA) has released detailed findings from the Phase 3 trial of the Johnson & Johnson (Janssen) vaccine candidate, Ad26.COV2.S (also known as, JNJ-78436735). The materials available include: a 119-page report prepared by Johnson & Johnson (Janssen), an 8-page addendum to the report, and a 62-page briefing document prepared by the FDA. On pages 12-13, the briefing document concludes: “As such, FDA has determined that the Sponsor has provided adequate information to ensure the vaccine’s quality and consistency for authorization of the product under an EUA.” Per the briefing document (page 12), the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) will meet on Friday, February 26, 2021, “to discuss and provide recommendations on whether based on the totality of scientific evidence available, the benefits of the Janssen Ad26.COV2.S vaccine outweigh its risks for use in individuals 18 years of age and older.” This is the criterion used by the FDA when determining whether to grant an Emergency Use Authorization (EUA) for a vaccine. We plan to report summarized safety and efficacy findings from this study within the next few days.

February 4, 2021: The U.S. Food and Drug Administration (FDA) announced that it will discuss Johnson & Johnson’s request for an emergency use authorization (EUA) for the Company’s vaccine candidate, AD26.COV2.S at a meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) on February 26, 2021. Background material will be made available to the public by February 24th. We will provide links to those materials on this site as soon as they become available. The meeting will be livestreamed on the FDA’s YouTube, Facebook and Twitter channels. We will provide links to these channels for those who wish to watch.

February 4, 2021: Johnson & Johnson announced that they have submitted an application to the US Food and Drug Administration (FDA) requesting an emergency use authorization (EUA) for their vaccine candidate, AD26.COV2.S. The Company plans to be ready to ship doses of the vaccine immediately after receiving authorization from the FDA. The Johnson & Johnson vaccine is a potentially important addition to the other vaccines currently available in the United States because it is estimated to be 85% effective in preventing severe COVID-19 after a single dose and it can be shipped using normal distribution channels. The Company estimates that the vaccine can be stored a standard refrigerator temperatures (36-46º F) for up to three months. 

January 29, 2021: Johnson & Johnson announced findings from the ENSEMBLE trial evaluating the safety and efficacy of a single dose of their vaccine candidate, AD26.COV2.S. This study was conducted in several countries, including the United States and South Africa. In the United States, a single dose of this vaccine was found to be 72% effective in preventing moderate to severe COVID-19 beginning 28 days after vaccination. The effectiveness of the vaccine in preventing moderate to severe COVID-19 was 66% in Latin America and 57% in South Africa. (When averaged across all study sites the vaccine was found to be 66% effective in preventing moderate to severe COVID-19 and 85% effective in preventing severe COVID19. No deaths related to COVID-19 were reported in the vaccine group, whereas 5 COVID-19-related deaths occurred in the placebo group.) The Company also reported that the vaccine was well-tolerated and that no safety concerns were identified.

The ENSEMBLE trial included nearly 44,000 participants, with 34%  of participants over age 60. In their press release, the Company stated: “The study enrolled 44% (N=19,302) of participants in the United States, 41% (N=17,905) in Central and South America (Argentina, Brazil, Chile, Colombia, Mexico, Peru) and 15% (N=6,576) in South Africa.” The table below shows the race/ethnicity of study participants, both globally and for the US only.

Race/Ethnicity Globally US Only
White/Caucasian 59% 74%
Hispanic/Latinx 45% 15%
Black/African American 19% 13%
Native American 9% 6%
Asian 3% 1%

The Company reported that vaccine efficacy was mostly consistent across racial/ethnic and age groups, and across different variants of the virus and regions studied. In South Africa, about 95% of the COVID-19 cases observed among study participants were due to infection with a variant of the original SARS-CoV-2 virus from the B.1.351 lineage. It is unclear if the lower efficacy observed among South African participants was due to the vaccine providing less protection against these variants.

The Company is planning to file a request for an emergency use authorization (EUA) with the US Food and Drug Administration (FDA) in early February. This request will contain detailed findings from the study. Based on experience with the Pfizer-BioNTech and Moderna vaccines, we anticipate that the FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) will meet to review the EUA request in mid to late February. Materials submitted by Johnson & Johnson and the results of independent analyses conducted by FDA staff should be available to the public about two days before the VRBPAC meeting. 

If the EUA is granted, the Company expects to be able to meet all 2021 supply commitments. Notably, Johnson & Johnson was part of Operation Warp Speed and received $456 million for research to develop a vaccine and $1 billion to deliver 100 million vaccine doses.

In addition to the ENSEMBLE trial described above, Johnson & Johnson is conducting the ENSEMBLE 2 trial which is studying the safety and efficacy of a two-dose regimen of the AD26.COV2.S vaccine. Enrollment of study participants in ENSEMBLE 2 began on November 15, 2020.

December 17, 2020: Johnson & Johnson announced that enrollment in the ENSEMBLE study has been completed. This study is evaluating a single dose of the vaccine candidate AD26.COV2.S. About 45,000 people have been enrolled in the study. The company expects to be able to report interim findings from the study by the end of January 2021. However, this will depend on the rate at which people in the study get moderate/severe COVID-19. (The protocol for this study states that the first interim analyses will be performed when 20 people in the study have developed moderate/severe COVID-19. If the vaccine is effective, most of these cases will occur among people who received the placebo vaccine.)

If the data support the safety and efficacy of the AD26.COV2.S vaccine, the company expects to submit an application for an Emergency Use Authorization (EUA) to the US Food and Drug Administration in February. If a EUA is approved, AD26.COV2.S would become the third vaccine approved for use in the US and it would be the first to require only a single dose. It is important to remember, however, that no safety or efficacy data have yet been reported from the study. 

The Company intends to file for U.S. Emergency Use Authorization (EUA) in early February and expects to have product available to ship immediately following authorization. It expects to share more information on specifics of deployment as authorizations are secured and contracts are finalized. The Company’s anticipated manufacturing timeline will enable it to meet its 2021 supply commitments, including those signed with governments and global organizations.

November 15, 2020: Johnson & Johnson announced a second global Phase 3 study of its candidate vaccine, Ad26.COV2.S. This vaccine is also known as JNJ-78436735. This new study will evaluate a 2-dose vaccine regimen. The new study is called ENSEMBLE 2. See Table 1 under Phase 3 Studies for more details about the study.

October 23, 2020: Johnson & Johnson announced that it is preparing to resume recruitment in the United States in its Phase 3 trial of the candidate vaccine, Ad26.COV2.S. This vaccine is also known as JNJ-78436735. This trial is called the ENSEMBLE trial. The temporary pause was triggered when one study participant developed a serious medical event. The nature of the event was not disclosed due to patient privacy concerns. The company reported that no clear cause for the event could be identified and that there was no evidence that the vaccine caused the event. The Data Safety and Monitoring Board (DSMB) overseeing this trial determined that it was safe to resume recruitment. The U.S. Food and Drug Administration (FDA) agreed with this decision. The company is in discussion with other regulatory agencies around the world to resume the study in other countries.

October 12, 2020: Johnson & Johnson paused its Phase 3 trial of the investigational vaccine, Ad26.COV2.S. This trial is called the ENSEMBLE trial. Until the trial is resumed, no new participants will be enrolled in the trial and no participants in the trial will be vaccinated. In large clinical trials, it is not unusual for some study participants to experience major medical events and these events often happen by chance. When a serious adverse event happens, the trial is paused to allow the Data Safety and Monitoring Board (DSMB) overseeing the trial, as well as regulatory agencies like the FDA, an opportunity to review data from the trial and determine if it is safe to resume. In their press release, Johnson & Johnson also provided information to clarify the difference between a “Study Pause” and a “Regulatory Hold”.

September 23, 2020: Johnson & Johnson announced the launch of its Phase 3 trial of the investigational vaccine, Ad26.COV2.S. This trial is called the ENSEMBLE trial. In the press release, Paul Stoffels, M.D., Vice Chairman of the Executive Committee and Chief Scientific Officer, Johnson & Johnson stated:  “We greatly value the collaboration and support from our scientific partners and global health authorities as our global team of experts work tirelessly on the development of the vaccine and scaling up our production capacity with a goal to deliver a vaccine for emergency use authorization in early 2021.”

Categories
Uncategorized

Where in the World?

The table below shows the vaccines that have been authorized for use around the world, as of April 11, 2021. The letter “A” indicates that the vaccine has been authorized only for emergency, early, or limited use in a location. The letter “B” indicates that the vaccine has received full market approval in a location.

The figures below provide information about the number of vaccine doses that have been administered around the world. We thank Our World in Data for providing free access to the data they collect and their interactive figures which bring the data to life.

To date, five geographic areas (United States, China, European Union, India, and United Kingdom) account for about 75% of the COVID-19 vaccines administered, while representing about 50% of the World population and 53% of confirmed COVID-19 deaths.

Categories
AstraZeneca Oxford

AstraZeneca Oxford COVID-19 Vaccine (AZD1222) Updates

  • March 25, 2021 (Thursday): AstraZeneca announced results of the primary analysis of data from the Phase 3 clinical trial evaluating the Company’s COVID-19 vaccine candidate, AZD1222, being conducted in the United States, Peru, and Chile. A brief summary of the design of this study can be found in Table 1 on this website and the full study protocol can be found here.

    The primary efficacy analysis included data from 32,449 study participants. The study counted cases of laboratory-confirmed symptomatic COVID-19 that were diagnosed at least 15 days after participants received the second dose of the vaccine. A total of 190 cases were observed. The Company reported that the vaccine was 76% effective in preventing symptomatic COVID-19. The Company also reported that the vaccine was 100% effective in preventing severe COVID-19/hospitalization. A total of 8 cases of severe COVID-19 were observed – all among participants who received the placebo vaccine. No safety concerns were identified. These findings are quite similar to those reported on March 22, 2021.

    The Company noted that 14 additional cases of possible/probable COVID-19 have been identified among study participants. These cases are currently being reviewed by experts to determine if they meet the criteria for “laboratory-confirmed, symptomatic COVID-19”. The experts reviewing these cases do not which participants received the AZD1222 vaccine. After the status of these 14 cases is resolved, the estimate of vaccine efficacy could increase or decrease a few percentage points.

    AstraZeneca is likely to submit the full results of their primary analyses to the US Food and Drug Administration (FDA) as part of a request for an Emergency Use Authorization (EUA) for the AZD1222 vaccine within the next two weeks. The full report submitted to the FDA, as well as a report prepared by the FDA after reanalyzing study data, is likely to be made available to the public in late April.
  • March 23, 2021 (Tuesday):  The National Institutes of Allergy and Infectious Diseases (NIAID) made the following announcement: “Late Monday, the Data and Safety Monitoring Board (DSMB) notified NIAID, BARDA, and AstraZeneca that it was concerned by information released by AstraZeneca on initial data from its COVID-19 vaccine clinical trial. The DSMB expressed concern that AstraZeneca may have included outdated information from that trial, which may have provided an incomplete view of the efficacy data. We urge the company to work with the DSMB to review the efficacy data and ensure the most accurate, up-to-date efficacy data be made public as quickly as possible. Authorization and guidelines for use of the vaccine in the United States will be determined by the Food and Drug Administration and Centers for Disease Control and Prevention after thorough review of the data by independent advisory committees.”

    In clinical trials, a DSMB is an independent panel of experts responsible for ensuring the quality of study design and implementation, as well as the safety of study participants. All of the COVID-19 vaccine clinical trials funded by the US government use the same DSMB. This DSMB has access to all of the data being collected. The DSMB can quickly stop a study if a study participant experiences an adverse event, determine whether the participant received the experimental vaccine or the placebo vaccine, and communicate with health care providers treating the participant to determine if the adverse event was likely to be vaccine related. DSMBs help to minimize bias when interpreting study results because DSMB members receive no funding from the vaccine manufacturers.Dr. Anthony Fauci appeared on Good Morning America today and briefly explained the background behind the NIH announcement. Although Fauci stated that information in the AstraZeneca press release on Monday, March 22nd. might not be completely accurate, he continues to believe data for the vaccine look quite good. He also emphasized that the US Food and Drug Administration (FDA) carefully reviews all study data before issuing an Emergency Use Authorization for a vaccine. This serves as a reminder that many safeguards are in place in the US to prevent the authorization of vaccines that have not been shown to be safe and effective.

 

  •  March 23, 2021 (Tuesday): In response to the NIAID announcement described above, AstraZeneca announced that the interim findings reported on Monday, March 22nd. were based on data collected before February 17, 2021. The Company stated that they are now working on the primary analyses and intend to announce the results from those analyses within the next two days. The Company also stated that findings from the primary analyses appear to be consistent with the interim analyses reported on March 22nd., but that the primary analyses have not yet been finalized.The timing of the announcement yesterday (Monday, March 22, 2021) is perplexing. According to the study protocol, the Company planned to perform the first interim analyses when 75 cases of symptomatic COVID-19 had occurred. They planned to perform the final analyses when 150 cases had occurred. This is similar to the study design used by Pfizer/BioNTech, Moderna, and Janssen (Johnson & Johnson). However, these other companies released findings from their interim analyses within days of when they reached the number of cases needed. It is not clear why AstraZeneca took over a month. In addition, the interim analyses included 141 cases of symptomatic COVID-19, nearly the number required for the primary analyses. Given that the Company is in the midst of finalizing the primary analyses, one has to wonder why they issued the press release yesterday based on interim findings.

 

  • March 22, 2021 (Monday): AstraZeneca announced interim findings from a Phase 3 trial investigating the Company’s vaccine candidate, AZD1222. This study was conducted in the United States and involved over 30,000 participants. Two-thirds of the people in the study received two doses of the AZD1222 vaccine, administered 4 weeks apart. The remaining participants received two doses of a placebo vaccine. About 20% of the people in the study were age 65 years or older.The announcement stated that 141 cases of symptomatic COVID-19 had occurred among study participants. However, the announcement did not state how many of these cases were among those who received the AZD1222 vaccine. Instead, the announcement simply states that the vaccine was 79% effective in preventing symptomatic COVID-19. No participants who received the AZD1222 vaccine were hospitalized or developed severe COVID-19. However, the announcement does not indicate whether anyone who received the placebo vaccine developed severe disease or were hospitalized. This makes it difficult to interpret the Company’s claim of 100% efficacy in preventing severe disease/hospitalization. (A CNN report issued on Tuesday, March 23rd. indicated that during a media briefing Dr. Anthony Fauci said that five cases of severe disease/hospitalization were reported in the placebo group.)

    The Company reported that no safety concerns had been identified. They looked at the risk of thrombotic events (blood clots) in detail and found no evidence that the AZD1222 vaccine increases the risk of thrombotic events among 21,583 participants who had received at least one dose of the vaccine. However, it is not clear why this safety information was presented for 21,583 participants, whereas efficacy analyses were based on more than 30,000 participants.

    The announcement stated that the Company is continuing to analyze the data and plans to submit results of the forthcoming primary analyses to the US Food and Drug Administration (FDA) as part of a request for an Emergency Use Authorization for the AZD1222 vaccine in the next few weeks.
  • March 11-19, 2021: On March 11th., the Danish Medicines Agency launched an investigation of the AstraZeneca vaccine (AZD1222) after reports of thromboembolic events (blood clots) in some people who had received the vaccine. As a precaution, the Agency placed a hold on use of the vaccine in Denmark until the investigation was completed. Over the next few days, several other countries followed suit and the European Medicines Agency (EMA) launched an investigation. On March 18th., EMA issued a statement reporting the conclusions from its preliminary review. EMA’s safety committee reviewed instances of blood clots reported as of March 16th. By that date, over 20 million people in the United Kingdom and the European Economic Area had received the vaccine. A total of 469 thromboembolic events have been reported after vaccination. (This includes thromboembolic events observed in clinical trials.) This number is lower than what would be expected based on how often people in the general public experience thromboembolic events. Therefore, the Committee concluded that the AstraZeneca vaccine does not increase the overall risk of blood clots. However, some uncommon types of blood clots were observed. Specifically, 7 cases of blood clots in multiple blood vessels (disseminated intravascular coagulation, DIC) and 18 cases of clots in the vessels draining blood from the brain (CVST) have been reported.  Most of these occurred in women under 55. These rates are higher than what would be expected in this age group. The Committee concluded that although the benefits of the vaccine continue to outweigh the risks, patients should be informed about the “remote” possibility (about 1 in a million) of developing DIC or CVST following vaccination. Product information for patients and health care providers is being updated to include more information about this possible risk. The following information for patients is taken directly from the EMA statement:
      • COVID-19 Vaccine AstraZeneca is not associated with an increased overall risk of blood clotting disorders.
      • There have been very rare cases of unusual blood clots accompanied by low levels of blood platelets (components that help blood to clot) after vaccination. The reported cases were almost all in women under 55.
      • Because COVID-19 can be so serious and is so widespread, the benefits of the vaccine in preventing it outweigh the risks of side effects.
      • However, if you get any of the following after receiving the COVID-19 Vaccine AstraZeneca:
        • breathlessness,
        • pain in the chest or stomach,
        • swelling or coldness in a leg,1
        • severe or worsening headache or blurred vision after vaccination,
        • persistent bleeding,
        • multiple small bruises, reddish or purplish spots, or blood blisters under the skin,
      • please seek prompt medical assistance and mention your recent vaccination.

    The World Health Organization (WHO) also conducted a thorough review of thromboembolic events following vaccination with the AstraZeneca vaccine. They issued a statement on March 19th. that concurred with the EMA report, emphasizing that while it is not known whether the vaccine caused the rare cases of DIC and CVST, close monitoring of this possible risk is needed.

    Since these reports were issued, most countries have lifted the holds they put in place on using the AstraZeneca vaccine.

  • January 5, 2021: The Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom published the full Public Assessment Report for the AstraZeneca vaccine candidate, AZD1222. It can be accessed here.
  • December 30, 2020: The Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom granted temporary approval for the AstraZeneca vaccine candidate, AZD1222, to be used in the UK. The conditions for the approval are available here. The Information for Healthcare Professionals sheet contains information from the interim analyses reported on November 23, 2020. To the best of our knowledge, findings from the final efficacy analyses are not yet available.
  • November 30, 2020: Since AstraZeneca released the findings from the first interim analysis for its COVID-19 vaccine candidate, AZD1222, on November 23rd, it has been reported that the most promising finding announced by the company (90% efficacy among people who received a half dose of the vaccine, followed by a full dose one month later) occurred by mistake. No one in the study was supposed to receive a half dose of the vaccine before the full dose. A company spokesperson quoted by Reuters said that all participants were supposed to receive two full doses of the vaccine. However, that does not match the information the company provided in ClinicalTrials.Gov. According to ClinicalTrials.Gov, the study being conducted in the United Kingdom was designed to test: (1) a single full dose of the vaccine; (2) a single full dose of the vaccine, followed by a half dose “booster” 4-6 weeks later; (3) two full doses of the vaccine, separated by a 4-6 week period; and (4) a single half dose vaccine for children age 5-12. The study being conducted in Brazil was designed to test: (1) a single full dose of the vaccine and (2) two full doses of the vaccine, separated by a 4-12 week period.In addition, after the company released its interim findings, it was discovered that only participants who were 55 years old or younger had received the half dose vaccine. So, we have no way to know if the vaccine would have been equally effective in older adults, who are most likely to develop severe COVID-19.Astra-Zeneca did not initially disclose the dosing mistake, contending that it didn’t matter whether the dosing change was done on purpose or not. However, it does matter!Scientific studies are designed to test specific hypotheses. These hypotheses must be stated at the start of the study, before any data are collected. If the scientists discover other interesting things when they are conducting the study, they use these discoveries to develop new hypotheses and design new studies to test them. That is simply how the scientific process works. For this reason, the 90% efficacy reported for people who received the half dose vaccine should be viewed with skepticism.Notably, AstraZeneca has not published the full protocols for the studies being conducted in the United Kingdom or Brazil. Hopefully, they will make these available to the public soon. It would also be helpful to see the interim findings broken down by: (1) country (United Kingdom/Brazil), (2) age groups identified in the ClinicalTrials.Gov records for these studies, and (3) each dosing regimen examined.Despite these concerns, the interim analyses suggest that the 2 full dose regimen of AZD1222 may reduce the risk of developing symptomatic COVID-19 by 62%. This is better than the minimal threshold of 50% efficacy recommended by the Food and Drug Administration (FDA). Although this level of efficacy is lower than the vaccines developed by Pfizer and Moderna, the AstraZeneca vaccine can be stored at normal refrigerator temperatures (36-46° F) for at least six months and is less expensive to manufacture than the Pfizer and Moderna vaccines. Therefore, the AstraZeneca vaccine still has the potential to play a significant role in bringing the COVID-19 pandemic under control.
  • November 23, 2020: AstraZeneca announced results from an interim analysis of its COVID-19 vaccine candidate, AZD1222. The analysis included data from studies being conducted in the United Kingdom and Brazil. A total of 131 COVID-19 cases were included in the interim analysis. The company reported findings from two different dosing regimens. Among participants who received a half-dose of the vaccine, followed by a full dose one month later, vaccine efficacy was 90%. Among participants who received a full dose of the vaccine followed by a full dose one month later, vaccine efficacy was 62%. These findings are difficult to interpret because data from two countries were combined and different dosage regimens are being tested in these countries. It would be helpful to have the efficacy estimates reported separately for each country. In addition, in both countries, the studies are also evaluating the efficacy of a single dose regimen. No data concerning the effectiveness of the single dose regimen were reported.  
  • November 5, 2020: First results from Phase 3 trials for the AstraZeneca Oxford COVID-19 vaccine, AZD1222, are expected in the fourth quarter of 2020. (Note: This link opens to a slide presentation in pdf format. Information about AZD1222 appears on Slides 25 and 31.)
  • October 23, 2020: Clinical trials for the AstraZeneca Oxford COVID-19 vaccine candidate, AZD1222, resumed in the United States after the Food and Drug Administration (FDA) completed review of all safety data from trials being conducted around the world and determined that it was safe to resume the trial.
  • October 2, 2020: A Phase I/II clinical trial for the AstraZeneca Oxford COVID-19 vaccine candidate, AZD1222, resumed in Japan, with approval of the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Trials had previously been resumed in the United Kingdom, Brazil, South Africa, and India.
  • September 12, 2020: Clinical trials for the AstraZeneca Oxford coronavirus vaccine candidate, AZD1222, resumed in the United Kingdom after the Medicines Health Regulatory Authority (MHRA) determined that it was safe to do so.
  • September 9, 2020: A participant in a clinical trial for the AstraZeneca Oxford COVID-19 vaccine candidate, AZD1222, developed an unexplained illness. The illness was identified as part of standard procedures used in all clinical trials to ensure the safety of study participants. Immediately after the illness was identified, the developers voluntarily paused all clinical trials of the vaccine being conducted around the world. In an interview with NBC News, Dr. Francis Collins, Director of the National Institutes of Health, identified the illness as transverse myelitis and explained that the illness may not have been caused by the vaccine. In large clinical trials, illnesses often happen by chance. This pause in the study will allow data safety committees and regulatory agencies like the FDA an opportunity to review data from the trials to determine if it is safe to continue enrolling participants.
  • August 31, 2020: Enrollment began in the US Phase 3 trial for the AstraZeneca Oxford COVID-19 vaccine candidate, AZD1222.  Phase 3 trials of AZD1222 had begun previously in the UK, Brazil and South Africa.

Around the World

  • October 1, 2020: The European Medicines Agency (EMA) announced that it had started a “rolling review” of data from studies involving AstraZeneca’s vaccine candidate, AZD1222. The EMA is the equivalent of the Food and Drug Administration in the United States. According to the EMA announcement, “A rolling review is one of the regulatory tools that EMA uses to speed up the assessment of a promising medicine or vaccine during a public health emergency. Normally, all data on a medicine’s effectiveness, safety and quality and all required documents must be submitted at the start of the evaluation in a formal application for marketing authorisation. In the case of a rolling review, EMA’s human medicines committee (CHMP) reviews data as they become available from ongoing studies, before a formal application is submitted. Once the CHMP decides that sufficient data are available, the formal application should be submitted by the company. By reviewing the data as they become available, the CHMP can reach its opinion sooner on whether or not the medicine or vaccine should be authorised.”
Categories
Bharat Biotech

Bharat Biotech COVID-19 Vaccine (Covaxin) Updates

  • March 3, 2021: Bharat Biotech announced interim findings from  the Phase 3 study testing the Company’s COVID-19 vaccine candidate, COVAXIN (also known as BBV152). This is an inactivated vaccine that requires two doses, separated by a 4-week period.

    • A total of 25,800 people took part in the study. All study participants were recruited in India. More information about the study can be in Table 1 on this website.
    • 43 people in the study developed laboratory-confirmed, symptomatic COVID-19 beginning 14 days after they received the second dose of the vaccine. Of these, 36 had received the placebo vaccine and 7 had received COVAXIN. Thus, the vaccine is estimated to reduce the risk of getting symptomatic COVID-19 by 80.6%.
    • No serious safety concerns have been reported.
    • Going forward, the Company plans to conduct final analyses when a total of 130 people in the study have developed COVID-19. 
  • January 3, 2021: Bharat Biotech announced that the Company’s COVID-19 vaccine candidate, COVAXIN (also known as BBV152), has been approved for emergency use in India. Approval was based on promising safety and immune response (immunogenicity) findings from early stage (Phase 1 and 2) studies involving about 1,000 study participants. Findings from these studies can be accessed using two links below.Safety and immunogenicity clinical trial of an inactivated SARS-CoV-2 vaccine, BBV152 (a phase 2, double-blind, randomised controlled trial) and the persistence of immune responses from a phase 1 follow-up report
    A Phase 1: Safety and Immunogenicity Trial of an Inactivated SARS-CoV-2 Vaccine-BBV152   
Categories
Moderna

Moderna COVID-19 Vaccine Updates

 

Summary of findings from Phase 3 trial evaluating the Moderna COVID-19 vaccine is available here. Data from this study were analyzed by the US Food and Drug Administration (FDA) before it issued an emergency use authorization for this vaccine.

Studies in Children

  • February 25, 2021: Moderna announced that it has completed enrollment of 3,000 adolescents aged 12-17 in a Phase 2/3 study evaluating the safety and efficacy of the mRNA-1273 vaccine in this age group. All participants have been recruited in the United States. This study is called the TeenCOVE study, after the original COVE study conducted in people age 18 and over. The company is planning to begin a third study (KidCOVE) focusing on children between the ages of 6 months and 11 years in the near future.

 

Development of Variant-Specific Vaccines

  • February 24, 2021: Moderna announced that it has completed manufacture of a vaccine candidate tailored to protect against the B.1.351 variant of the SARS-CoV-2 virus first identified in the Republic of South Africa. The variant-specific vaccine is called mRNA-1273.351. The Company has shipped doses of the variant-specific vaccine to the National Institute of Allergy and Infectious Disease (NIAID) at the National Institutes of Health (NIH). NIAID will perform a small clinical trial (Phase 1) to determine if the mRNA-1273.351 vaccine boosts immunity against the South African variant. Moderna envisions offering the mRNA-1273.351 vaccine as a booster for people who have already received the original vaccine or making a multivalent vaccine that would include the original vaccine and the variant-specific vaccine in a single shot. This type of multivalent (or combined) vaccine strategy is currently used for vaccines to prevent many other conditions, including influenza.


Efficacy Against Different Strains of SARS-CoV-2

  • January 26, 2021: Moderna announced results from a recently conducted in vitro study demonstrating that the Moderna vaccine, mRNA-1273, is likely to be effective in preventing infection from variant strains of the SARS-CoV-2 virus identified in the United Kingdom (called B.1.1.7) and South Africa (called B.1.351). Both of these variants of the SARS-CoV-2 virus have caused concern because they appear to be more contagious than the original virus. Although Moderna believes that the mRNA-1273 vaccine will provide protection against all variants of the SARS-CoV-2 virus identified to date, the recent study found that the mRNA-1273 vaccine, produces fewer neutralizing antibodies in response to the South African variant of the virus than in response to the original virus. This suggests than the vaccine may provide less protection against the South African variant of the virus. Therefore, the company has started to evaluate strategies to enhance vaccine efficacy. These include: determining if an additional booster dose of the mRNA-1273 vaccine increases the production of neutralizing antibodies against emerging virus strains including the B.1.351 variant and testing the efficacy of a modified vaccine (mRNA-1273.351) against the B.1.351 variant.

 Timeline for FDA Application and Availability of Vaccine to the Public

  • December 17, 2020: The US Food and Drug Administration (FDA) Vaccines and Related Biological Products Advisory Committee (VRBPAC) recommended that an emergency use authorization (EUA) be issued for the Moderna candidate vaccine, mRNA-123. The committee voted on the following question: “Based on the totality of scientific evidence available, do the benefits of the Moderna COVID-19 Vaccine outweigh its risks for use in individuals 18 years of age and older?” The vote was 20-Yes, 0-No, and 1-Abstention. (Note: Although Moderna recently started enrolling children age 12-17 into the trial, data from these participants are not yet available. That is why the question was limited to individuals age 18 or older.) It is likely that the FDA will issue the EUA tomorrow. The Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) is scheduled to meet on Saturday and Sunday of this week to vote on recommended uses of the Moderna COVID-19 vaccine under the EUA. The agenda for this meeting can be accessed here. The meeting will be live streamed and can be viewed here.
  • December 15, 2020: The US Food and Drug Administration (FDA) has released detailed findings from the Phase 3 trial of the Moderna candidate vaccine, mRNA-1273. An 84-page document prepared by Moderna is available here and a 7-page addendum to this document is available here.  A 54-page document prepared by the FDA is available here. On page 11 of this document the FDA states: “FDA has determined that the Sponsor has provided adequate information to ensure the vaccine’s quality and consistency for authorization of the product under an EUA” (Emergency Use Authorization). On page 12, the FDA states that the vaccine is proposed “for active immunization for the prevention of COVID-19 caused by SARS-CoV-2 in individuals 18 years of age and older.” We plan to report summarized safety and efficacy findings for the full sample and for different subgroups within the next few days.
  • November 30, 2020: Moderna announced that it plans to submit a request to the US Food and Drug Administration (FDA) today for an Emergency Use Authorization (EUA) for its candidate vaccine, mRNA-1273. In their primary efficacy analyses, 196 cases of laboratory-confirmed symptomatic COVID-19 occurred. Of these 185 occurred among people who received the placebo vaccine and 11 occurred among those tho received the mRNA-1273 vaccine, resulting in an estimate of vaccine efficacy of 94.1%. Of the 196 cases of symptomatic COVID-19 that occurred, 30 were classified as SEVERE COVID-19, all of which occurred in the placebo group.
  • November 11, 2020: Moderna reported that it has enough data for the first interim analysis from the Phase 3 trial of its experimental COVID-19 vaccine (mRNA-1273). It had submitted trial data to the independent board monitoring its trial, a sign that results could be announced shortly. The company said it expects this first interim analysis to include “substantially more than 53 cases,” which was the targeted trigger point for the analysis.
  • November 11, 2020: Dr. Anthony Fauci predicted that Moderna could have data from the Phase 3 trial of its COVID-19 vaccine (mRNA-1273) anywhere between “a couple of days” to “a little more than a week”.
  • October 22, 2020: According to a CNN report, Moderna’s president, Dr. Stephen Hoge, stated that “if all the stars align”, Moderna will apply for an emergency use authorization (EUA) for its COVID-19 vaccine (mRNA-1273) from the Food and Drug Administration (FDA) in early December 2020.

    Milestones to Reach Before FDA Submission

    53 study participants must develop laboratory-confirmed, symptomatic COVID-19.

    At least 40 of these 53 people (75%) must be in the control group (that is, they received a placebo vaccine).

    At least 15,000 study participants (50%) must be followed for at least 8 weeks after receiving their second dose of vaccine to assess possible side effects.

     
  • September 30, 2020: Moderna CEO, Stéphane Bancel told the Financial Times that Moderna will not seek an emergency use authorization for its COVID-19 vaccine (mRNA-1273) from the Food and Drug Administration (FDA) before November 25, 2020.

Interim Results

  • November 30, 2020: Moderna announced that it has completed the primary efficacy analysis for the Phase 3 study (known as the COVE study) testing its COVID-19 vaccine candidate, mRNA-1273.
    • A total of 196 people in the study developed laboratory-confirmed, symptomatic COVID-19. Of these, 185 had received the placebo vaccine and 11 had received the mRNA-1273 vaccine. Thus, they estimated that the vaccine reduces the risk of getting symptomatic COVID-19 by 94.1%.
    • In addition, a total of 30 people in the study developed severe COVID-19. All 30 had received the placebo vaccine.
    • No serious safety concerns have been reported.
    • Today, the Company will submit materials requesting a Emergency Use Authorization (EUA) for the mRNA-1273 vaccine from the United States (US) Food and Drug Administration (FDA). The Company expects these materials to be reviewed by the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) on December 17, 2020.
    • The Company expects to have about 20 million doses of the mRNA-1273 vaccine available in the United States by the end of 2020 and remains on track to manufacture 500 million to 1 billion doses globally in 2021.
  • November 16, 2020: Moderna announced results of the first interim analyses for its COVID-19 vaccine candidate, mRNA-1273. They reported that the vaccine was 94.5% effective in preventing laboratory-confirmed, symptomatic COVID-19. This study is known as the COVE study. More than 30,000 participants in the US are enrolled in the study. About half of these participants received the mRNA-1273 vaccine and the other half received a placebo vaccine.  95 participants in the study developed laboratory-confirmed COVID-19. Of these, 90 had received the placebo vaccine and 5 had received the mRNA-1273 vaccine. Of the 95 people in the study who developed COVID-19, 11 had severe COVID-19. All of the people who developed severe COVID-19 had received the placebo vaccine. No significant safety concerns were reported. The most common “severe” side-effects were: fatigue (9.7%), muscle pain (8.9%), and joint pain (5.2%). A “severe” side effect was defined as one that prevented a participant from doing routine daily activities on at least one day following an injection.
  • November 16, 2020: Moderna announced new data showing that its COVID-19 vaccine candidate, mRNA-1273, is more stable than originally estimated. The new data show that the vaccine remains stable:
    • At standard freezer temperatures (-4º F) for 6 months,
    • At standard refrigerator temperatures (36º to 46º F) for 30 days, and
    • At room temperature for up to 12 hours.

This better than expected stability will make it easier to distribute the vaccine to sites where it can be administered. It will also make it easier for doctors, nurses and pharmacists to store and administer the vaccine. In addition, the greater stability will likely result is less waste. The vaccine will come in vials than contain 5 doses. Once a vial is removed from the freezer, health care providers will have 30 days to use all 5 doses.

Continue reading “Moderna COVID-19 Vaccine Updates”

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Sinopharm Updates

February 25, 2021: The National Medical Products Administration in China has approved use of a second COVID-19 vaccine developed by Sinopharm. This is an inactivated vaccine developed in collaboration with the Wuhan Institute of Biologics. Sinopharm reported that the vaccine is 72.51% effective. However, no data from the Phase 3 studies evaluating this vaccine have been released to the public and no study findings have been published in the peer-reviewed scientific literature. Therefore, it is not possible to determine whether this estimate of vaccine efficacy is valid or reliable.

January 2, 2021: The National Medical Products Administration in China has approved use of a COVID-19 vaccine developed by Sinopharm. This is an inactivated vaccine developed in collaboration with the Beijing Institute of Biological Products. Sinopharm reported that the vaccine is 86% effective in preventing all cases of COVID-19 and 100% effective in preventing moderate and severe cases. It is not clear if asymptomatic cases were included in the analyses or if symptomatic cases needed to be confirmed by laboratory testing.  In previous reports, the vaccine was reported to be 79.34% effective. The Company stated that the discrepancy between the two estimates was due to differences in study methods used in different countries. Unfortunately, no data from the Phase 3 studies evaluating this vaccine have been released to the public and no study findings have been published in the peer-reviewed scientific literature. Therefore, it is not possible to determine whether the estimates of vaccine efficacy are valid or reliable.

 

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CoronaVac Sinovac

Sinovac (CoronaVac) Updates

February 21, 2021: To date, findings from Phase 3 studies involving the Sinovac Biotech COVID-19 vaccine candidate, CoronaVac, have not yet been published in the peer-reviewed scientific literature.

February 8, 2021: Sinovac Biotech, a China-based biopharmaceutical company focused on vaccine development, announced that its COVID-19 vaccine candidate, CoronaVac, has been granted a conditional marketing authorization from the China National Medical Products Administration. The vaccine is authorized for use in individuals aged 18 and above. The announcement made by the Company stated that authorization was based on findings from two months of follow-up data from Phase 3 studies. However, the announcement did not contain data concerning vaccine safety and efficacy.

February 5, 2021: Sinovac Biotech, a China-based biopharmaceutical company focused on vaccine development, announced findings from Phase 3 studies evaluating its COVID-19 vaccine candidate, CoronaVac. A total of 25,000 people recruited in Brazil, Turkey, Indonesia, and Chile have participated in these trials.  (See Table 1 Under Phase 3 Studies for more detailed information about the design of these studies). Only data from Brazil and Turkey were included in the press release. The Company reported that in the trials conducted in Brazil and Turkey, the CononaVac vaccine was 50.65% effective in preventing all cases of COVID-19, 83.70% effective in preventing cases that required medical care, and 100% effective in preventing hospitalization and death. These estimates were based on people who had received two vaccine doses approximately 14 days apart. Although the announcement indicates that 253 cases of COVID-19 were observed, the efficacy analyses only included cases that occurred at least 14 days after participants received their second dose. And, at the time of the analysis, many study participants had not yet received their second dose. Therefore, it is not possible to determine how many study participants or cases were included in the efficacy analysis. We look forward to reviewing more detailed study findings.

 

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Moderna

Novavax COVID-19 Vaccine Updates

Interim Study Findings and Timeline for FDA Application

  • January 28, 2021: Novavax presented information concerning the status of the Phase 3 study of its vaccine candidate, NVX-CoV2373, being conducted in the United States and Mexico. This study is testing a 2-dose regimen, with the doses administered 3 weeks apart. The Company plans to enroll a total of 30,000 study participants, with two-thirds of the participants receiving the NVX-CoV2373 vaccine.
    • As of January 27, 2021, a total of 16,748 people had been enrolled. The Company expects enrollment to be completed during the first half of February 2021 and that preliminary results may be available by April 2021.
    • The Company expects the NVX-CoV2373 vaccine to be approved for emergency use first in the United Kingdom (UK) based on findings from the study reported below. However, the Company is also discussing the types of data needed to obtain an emergency use authorization in other countries around the world, including the United States.
    • In the United States, the Food and Drug Agency could consider approving the NVX-CoV2373 vaccine for emergency use based on data from the UK study. In this case, emergency use authorization could be granted before the end of March 2021. 
    • Novavax is part of Operation Warp Speed and obtained $1.6 billion for vaccine research and the manufacture of 100 million vaccine doses.
  • January 28, 2021: Novavax announced the results of interim analyses from the Phase 3 study of its vaccine candidate, NVX-CoV2373, being conducted in the United Kingdom (UK). This study is testing a 2-dose regimen, with the doses administered 3 weeks apart. The study enrolled more than 15,000 people between the ages of 18 and 84.
    • In the interim analyses, the vaccine was nearly nearly 90% effective in preventing symptomatic COVID-19, beginning 7 days after the second dose. A total of 62 cases of symptomatic COVID-19 were observed (56 in the placebo group and 6 in the NVX-CoV2373 group). Only one participant developed severe COVID-19. This participant was in the placebo group.
    • Of the 62 cases observed, 32 were caused by the UK variant of the SARS-CoV-2 virus and 24 were caused by the original virus first identified in Wuhan, China. (In the remaining 6 cases, the virus has not been sequenced.) Vaccine efficacy was estimated at 95.6% against the original virus and 85.6% against the UK variant.
    • No safety concerns were identified.
    • The final analyses will be conducted when a total of 100 cases have been observed.
  • November 9, 2020: Novavax announced that its COVID-19 vaccine candidate, NVXCoV2373, has been granted Fast Track Designation by the US Food and Drug Administration (FDA). The Fast Track process is designed to streamline FDA review of new drugs and vaccines that may help treat or prevent a serious health problem. The goal is to get drugs and vaccines to patients as quickly as possible without compromising safety.

Participant Enrollment

  • October 27, 2020: Novavax announced that 5,500 people have been enrolled in the Phase 3 trial being conducted in the United Kingdom to test its COVID-19 vaccine candidate, NVXCoC2373. (For more information about this study, see Table 3 under Phase 3 studies.) The company increased the planned number of study participants from 9,000 to 15,000 and expects to have all participants enrolled by the end of November 2020. This is an event-driven study. The first interim analysis will be performed when at least 66 people in the study have developed laboratory-confirmed symptomatic COVID-19. With the increase in the number of study participants, the company expects to be able to conduct their first interim analysis as soon as the first quarter (January-March) of 2021.

Around the World

  • November 4, 2020: Novavax announced that it has signed a non-binding agreement with the Australian Government to supply 40 million doses of the company’s vaccine candidate, NVXCoC2373. The vaccine could be delivered as soon as the first half (January-June) of 2021. The agreement depends on whether the vaccine is shown to be safe and effective in ongoing Phase 3 trials and is approved for use by Australia’s Therepeutic Goods Administration (TGA). The TGA is equivalent to the Food and Drug Administration (FDA) in the United States. Novavax has established similar agreements with the governments in other countries, including: the United States, the United Kingdom, and Canada. They have also established agreements with partners to distribute the vaccine in Japan, South Korea, and India.