General Information on COVID-19 Vaccine Development

1. ACIP recommended that COVID-19 vaccines can be coadministered with other vaccines, including influenza vaccines in their 2021–22 Influenza Season update. A 679 patient, British Phase IV trial found that a COVID-19 vaccine given with an influenza vaccine on the same day in different arms will not affect the immune response of either vaccine. Adverse events were similar in patients that received both vaccines on the same day and patients that received one of the vaccines three-weeks later. The Pfizer-BioNTech and AstraZeneca COVID-19 vaccines were used in the study. Sanofi announced interim results from a trial where Sanofi’s Fluzone High-Dose Quadrivalent vaccine and Moderna’s COVID-19 mRNA investigational booster were co-administered. Immunogenicity and safety for both vaccines were similar to what is seen with either vaccine administered alone.
   
2. ACIP met to review the safety of the three COVID-19 vaccines that have received an EUA. The group recommended that the benefits of vaccination outweigh the risks for Guillain-Barré syndrome and thrombosis with thrombocytopenia syndrome after Janssen COVID-19 vaccination and myocarditis after mRNA (Pfizer-BioNTech and Moderna) COVID-19 vaccination.
3. The FDA may not review additional COVID-19 vaccines for emergency use if the sponsoring company is not already in discussions with the FDA. Novavax, Medicago and Astra Zeneca have discussed approval with the FDA. Other vaccine developers would need to seek full authorization.
4. British researchers are going to test the use of different COVID-19 vaccines for the first and second doses. One trial will give the Pfizer-BioNTech vaccine first and follow it with the AstraZeneca vaccine, while another cohort will receive the vaccines in reverse order. An AstraZeneca trial will evaluate the AZ vaccine with the Russian Sputnik V vaccine.
5. The Director of the Chinese Center for Disease Control and Prevention said the current Chinese COVID-19 vaccines offer low protection against the coronavirus. He also praised the mRNA vaccines and said China is working on developing mRNA vaccines.  Hundreds of millions of doses of Chinese vaccines have been distributed worldwide and 65 million Chinese citizens received at least one dose.
6. Anthony Fauci and Andy Slavitt have stated, the small studies supporting a single vaccine dose are too limited to change The U.S. recommendation for two doses of either the Pfizer-BioNTech or Moderna vaccines.
7. Researchers from Yale and the CDC analyzed COVID-19 vaccine efficacy in 463 nursing home residents during outbreaks at two Connecticut skilled nursing facilities. Vaccine efficacy was measured from 14 days after the first dose through seven days after the second, because there was not enough follow-up data to determine the impact of full vaccination. The researchers found the vaccines to be as effective as in the general adult population.
8. Researchers at Johns Hopkins analyzed a convenience sample of 436 transplant patients who were immunized with the Moderna or Pfizer COVID-19 vaccines and detected an antibody response about three weeks after the first immunization in only 17% of patients. Patients were more likely to develop antibodies if they were younger or received the Moderna vaccine. Patients were less likely to show an antibody response if they were receiving anti–metabolite maintenance immunosuppression (mycophenolate or azathioprine).
9. Animal studies suggest that an influenza-COVID-19 combination vaccine would elicit antibodies for both viruses at levels similar to that seen with the individual vaccines. The vaccine also prevented infection from a virus challenge.​
10. In a retrospective review of 39,156 asymptomatic patients, in the Mayo Clinic Health System, who were tested for COVID-19 for an upcoming procedure, 1.4% of vaccinated patients tested positive compared to 3.2% of unvaccinated patients for an 80% reduction in the development of asymptomatic COVID-19 with the vaccine.
11. CDC researchers analyzed results of COVID-19 tests from 3,950 health care workers and first responders to estimate real-world effectiveness of the COVID-19 mRNA vaccines. Vaccine effectiveness was found to be 80% after one immunization and 90% in fully vaccinated individuals.
12. Both Pfizer-BioNTech and Moderna have said that patients that received both doses of the mRNA COVID-19 vaccines will likely need a booster dose within a year. 
13. A retrospective analysis of 513,284 patients, found the incidence of cerebral venous thrombosis to be eight times more common in patients that developed COVID-19 than in patients that received the AstraZeneca vaccine and ten times more common than in patients that received the Pfizer-BioNTech or Moderna vaccine.
14. Researchers analyzed data from 417 patients, who were 65 or older and hospitalized with COVID-19 symptoms. 187 patients tested positive for COVID-19, while 230 were negative. When examining the impact of vaccination in preventing COVID-19 infection, efficacy was estimated to be 94% for fully vaccinated patients and 64% for patients that only received the first dose of the Pfizer-BioNTech or Moderna COVID-19 vaccines.
15. Both Pfizer-BioNTech and Moderna have said that patients that received both doses of the mRNA COVID-19 vaccines will likely need a booster dose within a year. 
16. In a 30 patient case series from Johns Hopkins, researchers examined the effect of a third mRNA COVID-19 vaccine dose on transplant patients. Antibody levels were measured before the third dose and most patients had negative antibody levels with six having low levels. The booster dose was given 67 days after the second vaccine dose. Half of the patients received the J&J vaccine, while the rest received one of the mRNA vaccines. All six low antibody level patients developed high antibody titers. In the 24-patient, negative antibody level group, 25% developed high titers, 8% developed low titers and 67% remained negative.
17. Three letters to the editor were published in the New England Journal of Medicine describing the effectiveness of the COVID-19 mRNA vaccines in healthcare settings.

• Among 36.659 health care workers in California, only 1% tested positive mostly in the first two weeks after the initial dose. Only 15 tested positive after the second dose.
• Researchers analyzed data from 23,234 healthcare workers in Texas and found that 1.8% of workers that had received just one vaccine and 0.05% of fully vaccinated workers tested positive for COVID-19 compared to 2.6% of unvaccinated employees. 
• In Israel, only 4 of 4,079 fully vaccinated healthcare workers, tested positive for COVID-19.
• In a 679 patient, British Phase IV trial found that a COVID-19 vaccine can be given with an influenza vaccine on the same day in different arms will not affect the immune response of either vaccine. Adverse events were similar in patients that received both vaccines on the same day and patients that received one of the vaccines three-weeks later. The Pfizer-BioNTech and AstraZeneca COVID-19 vaccines were used in the study.

The journal Nature provided a graphical description of the different types of methods to create a vaccine that are currently being used to work on a vaccine for COVID-19. Ultimately each vaccine elicits an immune response that leads to the production of antibodies.

• A whole virus vaccine uses a weakened or inactivated virus
• Viral vectors use a genetically modified virus to produce a virus protein that causes the immune response. The immune response may be weakened if a common virus is used which has a high degree of immunity in the community. As an example, it is speculated that if a modified adenovirus is used, a booster immunization may be required to maintain immunity.
• Nucleic acid vaccines use DNA or RNA to causes a cell to produce a protein that causes an immune response. Since the full virus is not produced, no infection develops. No approved vaccine currently uses this technology. While mRNA and DNA vaccines can be designed, manufactured and tested faster than typical vaccines, the vaccine design have not been proven to be efficacious or safe.
• Protein-based vaccines use a protein from the virus that will cause an immune response without infection. This type of vaccine requires an adjuvant to stimulate the immune response. No protein-based vaccine has been tested in a human.
• Virus-like particles are empty virus shells that mimic the virus structure, but do not have the genetic material to cause an infection. These vaccines can stimulate a strong immune response but are harder to manufacture.

The CDC has provided clinical considerations for the Pfizer-BioNTech, Moderna and Johnson & Johnson COVID-19 vaccines. 

• Two doses of the Pfizer-BioNTech vaccine are given 21-days apart to patients 16 and older
• Two doses of the Moderna vaccine are given 28-days apart to patients 18 and older
• A single dose of the Johnson & Johnson vaccine is given 28-days to patients 18 and older
• Delay vaccination of patients with an acute COVID-9 infection until the patient has recovered. Immunization may be delayed for up to 90 days.
• Patients that have received convalescent or COVID-19 antibodies should have their immunization delayed for 90 days.
• Immunocompromised, autoimmune or pregnant patients with no contraindications, may receive the vaccine. Potential risks should be discussed with the patient, such as the unknown vaccine safety profile and effectiveness in immunocompromised populations, as well as the potential for reduced immune responses.
• Patients with a history of anaphylactic reactions should be observed for 30 minutes after vaccination
• Patients with a history of allergic, but not anaphylactic reactions should be observed for 15 minutes after vaccination
• No other vaccines should be given within two weeks of the Pfizer-BioNTech vaccine.
• Patients with a history of Guillain-Barré syndrome or Bell’s palsy may receive the vaccine.
• The agency continues to recommend the interval between doses, three weeks for the Pfizer-BioNTech vaccine and four weeks for Moderna’s vaccine, should be followed as closely as possible.
• If a patient is late for the second dose, they should receive the second vaccine by week six. There is not enough information to make a recommendation beyond six weeks, but an extra dose should not be administered if the second dose is not given by then. 
• The Pfizer-BioNTech and Moderna vaccines are not considered interchangeable.  However, if the initial vaccine a patient received cannot be determined or is not available, another mRNA vaccine may be given at least 28 days after the first vaccination.
• It is preferable for a patient that received an mRNA vaccine to receive a second dose with an mRNA vaccine. But if no mRNA vaccine is available or there is a contraindication to receiving one, then the patient can receive the Johnson & Johnson vaccine for the second dose at least 28-days after the initial vaccination.
• Vaccination During Pregnancy and Lactation

• The American College of Obstetricians and Gynecologists (ACOG) recommends the Pfizer-BioNTech, Moderna or Johnson & Johnson COVID-19 vaccines should not be withheld from pregnant or lactating women who meet criteria for vaccination based on ACIP-recommended priority groups. A discussion with the patient of the vaccine should include the potential for adverse effects, hand washing and wearing a mask. Patients should be educated that an mRNA vaccine is not a live virus vaccine and no adjuvant is used in the Pfizer-BioNTech COVID-19 vaccine. The mRNA vaccines do not enter the nucleus and do not alter human DNA in vaccine recipients, so these types of vaccines cannot cause any genetic changes. The CDC also discusses mRNA vaccines on a dedicated web page. ACOG recommends the patient’s decision on whether to receive the vaccine should be supported.
• ​The CDC analyzed surveillance data from 30,494 patients who were vaccinated with either the Pfizer-BioNTech or Moderna COVID-19 vaccines during pregnancy and found the rates of complications were not significantly different from those of unvaccinated pregnant women.
• Researchers examined data from 30 pregnant, 16 lactating, and 57 non-pregnant/non-lactating patients and found the mRNA vaccine response was equivalent for pregnant and lactating women compared to non-pregnant/non-lactating women. Further, the immune transfer to neonates occurred via placental and breastmilk. Pregnant and lactating women also developed neutralizing antibodies that were active against the B.1.1.7 (U.K.) and B.1.351 (South African) variants.
• Researchers analyzed data from 35,691 pregnant women, who had received either the Pfizer–BioNTech or Moderna COVID-19 vaccines, that were enrolled in the V-safe Surveillance System and Pregnancy Registry and the Vaccine Adverse Event Reporting System (VAERS). Compared to nonpregnant women the incidence of injection-site pain was more frequent, while headache, myalgia, chills, and fever were less frequent. The rate of spontaneous abortion was 12.6%, which falls within the historical range of 10% to 26%. While not directly comparable, the rate of adverse pregnancy and neonatal outcomes after COVID-19 vaccination were similar to the rates reported before the COVID-19 pandemic. Based on data from the study, the CDC now recommends COVID-19 vaccination for pregnant women.
• A retrospective analysis of the outcomes of 15,060 pregnant women in an Israeli database found the estimated effectiveness of the Pfizer-BioNTech COVID-19 vaccine to be 78%.
• A study of 36 women, who received an mRNA vaccine during pregnancy, found that antibodies were passed on to infants.
• A case-control study involving 105,446 pregnancies, from eight large U.S. healthcare systems and an analysis of outcomes from 2,456 women enrolled in a CDC pregnancy registry found no increase in the risk for spontaneous abortion with COVID-19 vaccinations.

SARS-CoV-2 Variants
The WHO released simplified names for COVID-19 variants of interest and concern to make it easier to report and talk about these virus mutations in non-scientific reports and articles. The simplified labels use Greek letters to identify a variant. The CDC has added these new designations to its tables of variant classifications and definitions. The WHO lists both the new simple names along with scientific names on its variant tracking page. The current list of variants being tracked by the CDC and WHO include (Pango lineage designation, Region first detected, WHO label): 

1. B.1.1.7 (U.K.): Alpha variant
2. B.1.351 (South Africa): Beta variant
3. P.1 (Brazil): Gamma variant
4. B.1.617.2 (India): Delta variant
5. B.1.427 and B.1.429 (California): Epsilon variant
6. P.2 (Brazil): Zeta variant
7. B.1.525 (Nigeria): Eta variant
8. P.3 (Philippines): Theta variant
9. B.1.526 (New York): Iota variant
10. B.1.617.1 (India): Kappa variant

• Israeli researchers administered a single dose of the Pfizer-BioNTech COVID-19 vaccine to six patients that had recovered from a COVID-19 infection with the original Wuhan virus. Antibodies taken after recovery, but before vaccination were able to neutralize the original virus and the B.1.1.7 (U.K.) and P.1 (Brazil) variants, but not the B.1.351 (South African) variant. After vaccination, antibody titers were greatly increased and neutralized all strains of the virus.
• South African researchers tested the neutralizing activity of COVID-19 antibodies from 89 patients that had recovered from an infection with the B.1.351 (South African) variant. The antibodies were effective against both B.1.351 and P.1 (Brazil) variants. The researchers recommend that vaccines targeted at B.1.351 may offer cross-reactive neutralizing antibody responses to other known SARS-CoV-2 strains.
• Researchers from two vaccine manufacturers, Duke University and NIAID tested the neutralizing activity of antibodies from 14 recovered patients, 26 patients that received the Moderna COVID-19 vaccine and 23 patients that received the experimental Novavax COVID-19 vaccine. The researchers found that while neutralizing activity was modestly lower for the B.1.429 (California) variant, the activity was strong enough to neutralize the variant. The large magnitude of resistance observed with the B.1.351 (South African) variant was cause for concern.
• Researchers tested antibodies from recovered COVID-19 patients, fully mRNA (Pfizer-BioNTech and Moderna) vaccinated subjects and who received the Regeneron monoclonal antibody combination in neutralizing the B.1.526 (New York) variant. The B.1.526 variant, decreased titers, but was still neutralized by all four types of antibodies.
• Researchers from NIAID and their academic partners found that while virus neutralization from antibodies from 15 persons who had received the Moderna COVID-19 vaccine and 10 persons who had received the Pfizer–BioNTech vaccine were reduced the antibodies retained 79% of activity against the B.1.617.1 (India) variant and 96% of activity against the B.1.617.2 (India, Delta) variant.
• A 19,109 patient, British observational study described the effectiveness of COVID-19 vaccines against the Alpha and Delta variant. After two doses, the effectives of the Pfizer-BioNTech COVID-19 vaccine was estimated to be 93.7% for the alpha variant and 88% for the delta variant. The effectiveness of the AstraZeneca vaccine was estimated to be 74.5% for the alpha variant and 67% for the delta variant.
• The World Health Organization announced that COVID-19 vaccines currently approved in the U.S. and Europe are effective against virus variants. This includes the B.1.617 (India), B.1.351 (South Africa), B.1.1.7 (U.K.) and P.1 (Brazil).
• A CDC investigation of a July 2019 COVID-19 outbreak in Massachusetts found breakthrough infections in fully vaccinated patients. The infections occurred in patients that had attend multiple large public gatherings that included travelers from many areas. This led the CDC to recommend that everyone wear masks, regardless of vaccination status, in indoor settings where there is a high risk of COVID-19 transmission.
• A CDC analysis of 1,175 U.S. veterans aged 18 years or > from five Veterans Affairs Medical Centers found overall vaccine effectiveness against COVID-19–associated hospitalization to be 86.8% with similar effectiveness before (February 1–June 30) and after (July 1–August 6) Delta variant predominance. Effectiveness was 79.8% for patients 65 years or greater compared to 95.1% for patients 18 to 64 years.
• A CDC analysis of data from 32,867 patient visits in nine states from June to August 2021 found overall effectiveness to be 86% at preventing hospitalizations. Effectiveness was 76% for patients 75 years or greater compared to 89% for patients 18 to 74 years. Vaccine effectiveness to prevent hospitalization was highest for the Moderna vaccine at 95% compared to 80% for the Pfizer-BioNTech vaccine and 60% for the J&J vaccine.
• A CDC analysis of data from 569,142 viral infections in 13 states found a higher risk for COVID-19 infections, illness, and death in unvaccinated compared to vaccinated individuals.
• A pre-publication draft of a retrospective review of data from 1,914,670 patients in an insurance claims database estimated the vaccine effectiveness, for the J&J COVID-19 vaccine in states with high Delta variant incidence, at 78% for infections and 85% to prevent hospitalizations.

Myocarditis and Pericarditis

The CDC provides advice on myocarditis and pericarditis in adolescents and young adults who received an mRNA COVID-19 vaccine. Most cases have occurred in male patients 16 and older and patients responded well to treatment. The CDC continues to recommend vaccination of all patients 12 years and older due to the greater risk for complications from COVID-19. HHS, CDC and several professional societies published a statement in support of continued vaccination of all eligible patients 12 and older. The World Health Organization’s Global Advisory Committee on Vaccine Safety found the benefits of mRNA COVID-19 vaccines outweigh the risksin reducing hospitalizations and deaths from COVID-19. The risk for myocarditis and pericarditis is very low. Th estimate in patients 12 to 29 is 40.6 cases per million second doses among males and 4.2 cases per million among females. In patients over 30, the rate drops to 2.4 per million second doses in males and one per million second doses in females in patients.
 
Researchers have examined the incidence of myocarditis after mRNA COVID-19 vaccine immunization.

• A preliminary FDA review found reported cases of myocarditis/pericarditis have been consistent with the Pfizer-BioNTech COVID-19 vaccine clinical trials. The reported cases were greater than expected in patients 16 to 24. After the second dose, the incidence is estimated to be 16 cases per million doses.
• Researchers at Duke examined myocarditis in seven patients. Four of the patients had received two doses of an mRNA vaccine within the past five days. All four patients recovered without further problems. There were 561,197 patients that had received an mRNA vaccine during the study time period. The authors concluded that myocarditis is extremely rare.
• Military researchers examined myocarditis in 23 patients, that presented within four days of vaccination with an mRNA vaccine. Most patients (20) developed myocarditis after the second immunization. All patients recovered or were recovering at the time of the report. There were 2.8 million patients were vaccinated during the study time period. The authors concluded the incidence of myocarditis is small, but higher than expected.

Mixing Vaccines and Altering the Second Dose Duration

​Oxford University is examining the safety and efficacy of giving two different COVID-19 vaccines to provide evidence for when the use of two different vaccines is unavoidable and to determine optimal use of the vaccines. A preprint draft provides results from the first phase of the 830 patient, Com-COV trial, where the elicited immune response was measured after different combinations of Comirnaty (Pfizer/BioNTech COVID-19 vaccine) and Vaxzevria (AstraZeneca COVID-19 vaccine) were given 4 weeks apart and antibody levels measured 28-days after the second dose.

• The highest antibody titer was obtained from two doses of Comirnaty (14,080 ELU/ml)
• Vaxzevria followed Comirnaty had the second highest antibody titer (12,906 ELU/ml)
• Comirnaty followed by Vaxzevria had the third highest antibody titer (7,133 ELU/ml)
• Two doses of Vaxzevria elicited the lowest antibody titer (1,392 ELU/ml)

T cell responses measured by spot forming cells/1 million peripheral blood mononuclear cells were:

• Vaxzevria / Comirnaty 185 SFC/106 PBMCs
• Comirnaty / Vaxzevria 99 SFC/106 PBMCs
• Comirnaty / Comirnaty 80 SFC/106 PBMCs
• Vaxzevria / Vaxzevria 50 SFC/106 PBMCs

A second phase of Com-COV will examine elicited antibodies with the same combination of vaccines are given 12 weeks apart. 

COVID-19 Vaccine Booster Immunizations

The U.S. Department of Health and Human Services (HHS) announced the government’s plan for a booster (third) dose of the mRNA vaccines(Pfizer-BioNTech and Moderna) to begin in September, if approved by the FDA and recommended by ACIP. If approved, booster vaccinations would begin on September 20, 2021, with health care providers, nursing home residents, and other seniors, who received their second vaccine dose at least eight months ago. Data is still being examined for the Johnson & Johnson vaccine, but it is anticipated a booster will also be needed. The decision was based on three CDC studies.

• On 9/22/2021, the FDA amended the EUA for the Pfizer-BioNTech COVID-19 Vaccine to allow a booster dose, given at least six months after completion of the second dose to patients 65 years and older or who are at high risk for severe COVID-19, which includes healthcare professionals, frontline workers and people that live in group settings. On 9/23/2021, ACIP recommended a booster dose of the Pfizer-BioNTech vaccine for patients 65 years and older, residents of long-term care facilities and 50 to 64 years patients at high risk for severe COVID-19. Patients who at 18 to 49 at high risk for severe COVID-19 infection may receive one, if the patient wants one. ACIP did not recommend a booster dose for health care professionals, other front-line workers or people that live in group settings. The CDC agreed with ACIP on recommending a booster dose for patients 65 years and older, residents of long-term care facilities and patients at high risk for severe COVID-19, but also added a recommendation for health care professionals, other front-line workers or people that live in group settings. Neither the FDA nor CDC has recommended booster doses of the Moderna or Johnson & Johnson COVID-19 vaccines. No recommendation was made regarding use of the Pfizer-BioNtech vaccine as a booster dose for patients that originally received the Moderna or Johnson & Johnson COVID-19 vaccines.
• An analysis by the New York State Department of Health of COVID-19 infections in the state found that overall vaccine effectiveness declined from 91.7% to 79.8% with the effectiveness against hospitalization remaining high at 91.9% to 95.3%. The decline coincided with an increase in Delta variant cases to more than 80% by the end of the surveillance period in late July.
• A CDC analysis of COVID-19 infections among long-term care (LTC) facility residents found a decrease in effectiveness of mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna) with the Delta variant. In March to early May before widespread circulation of the Delta variant, the combined effectiveness of the vaccines was 74.7%. Effectiveness decreased to 67.5% when Delta began circulating in mid-May to mid-June. From mid-June to the beginning of August, the Delta variant was the predominant strain and vaccine effectiveness had decreased to 53.1% among LTC residents.
• The CDC analysed COVID-19 infections from 21 hospitals in 18 states and found the vaccine effectiveness for the mRNA COVID-19 vaccines to be 86% overall during the 24-week surveillance period in spring and early summer 2021. Effectiveness was 90% for immune-competent patients and 63% for immunocompromised patients. Vaccine effectiveness did not have a significant change over time. Genome analysis found 53.3% of infections were due to the Alpha variant and 16.3% were due to the Delta variant. By mid-June, the Delta variant had become the dominant strain.
• In a Viewpoint article in Lancet, Marion Gruber and Philip Krause, FDA top vaccine reviewers who recently announced their retirements, along with members of the WHO argued that data does not support administering a booster dose of COVID-19 vaccines. They feel that efficacy has not waned enough to justify a booster dose, we do not know enough about the safety and efficacy of a booster dose and reiterate WHO’s call for all countries to be vaccinated before booster doses are given.
• In a review of data from 1,137,804 patients from the Israeli Ministry of Health database, found that a booster dose of the Pfizer/BioNTech COVID-19 vaccine, given at least five months after the second dose in patients 60 years or older, resulted in a reduction in confirmed and severe cases of COVID-19, during the first 12 days after the third dose.
• In a six-month follow-up of the pivotal trial for the Pfizer/BioNTech COVID-19 vaccine (NCT04368728), vaccine efficacy was 91.3%.  Vaccine efficacy gradually decreased over time, but efficacy for severe disease remained high at 96.7% and 100% for the Beta variant. Overall efficacy was 84% from month four to six.
• A third (booster) dose of the Pfizer/BioNTech COVID-19 vaccine was given to the pivotal trial population (NCT04368728), 7.9 to 8.8 months after the second dose. Antibody titers increased after the third dose for the original SARS-CoV-2 strain and variants.
• A review by the FDA for the Vaccines and Related Biological Products Advisory Committee (VRBPAC) found a third dose of the Pfizer-BioNTech vaccine to be safe and well tolerated. The review questioned whether the available data and quality of the studies support a need for a third (booster) dose of the vaccine, since there is still adequate protection from severe COVID-19 and death.
• The FDA VRBPAC voted 16 to 2 to recommend approval of a booster dose of the Pfizer-BioNtech COVID-19 vaccine, given 6-months after the second dose, in patients 65 years and older. The committee also voted 18 to 0 to recommend a booster dose for younger patients at high risk for severe COVID-19.
• The CDC analyzed surveillance data from 12,591 patients enrolled in V-Safe, who received a booster vaccination of the Pfizer-BioNTech COVID-19, vaccine and found the occurrence of adverse events to be similar to ADR experienced after the second dose.

Some of the more advanced vaccine projects include:

​AstraZeneca and the University of Oxford are developing a vaccine (AZD1222) created by the University of Oxford that uses a non-replicating chimpanzee adenovirus, that is not infectious to humans. The adenovirus is genetically modified to contain COVID-19 spike proteins. AstraZeneca agreed to sell its COVID-19 vaccine near cost and may be charging as low as $3 per dose. AstraZeneca has agreements with Brazil, Argentina and Mexico to manufacturer AZD1222 to supply patients in Central and South America. The EMA has started a rolling review of AstraZeneca’s COVID-19 vaccine with early non-clinical data, while the FDA still has a hold in place for the U.S. Phase III trial.

1. AZD1222 is also listed as ChAdOx1 nCoV-19
2. The U.S. will share its stockpile of the AstraZeneca COVID-19 vaccine with other countries. Up to 60 million doses are expected to be available.
3. The World Health Organization (WHO) has endorsed the AstraZeneca COVID-19 vaccine and recommends two doses, given eight to 12 weeks apart.
4. In a 56-day, 1,077 patient, Phase I/II, British trial (NCT04324606), neutralizing antibody levels after a single dose of AstraZeneca’s and the University of Oxford’s AZD1222 vaccine, peaked at 28-days and remained elevated through day 56 with 90% of participants developing antibodies. A booster dose was given four weeks later to 10 patients and resulted in higher antibody levels. Many patients developed systemic reactions (e.g., chills, fever) compared to meningococcal conjugate vaccine, but the reactions were reduced with acetaminophen. 
5. Results from the 500 patient, Phase II portion of a 12,390 patient, Phase II/III trial found that AZ’s AZD1222 elicited similar antibody titers in all age groups. The vaccine was well tolerated and older patients had fewer adverse reaction than younger patients.
6. An interim analysis of data from 11,636 patients participating in four trials (NCT04324606, NCT04400838, NCT04444674, ISRCTN89951424) evaluating AstraZeneca’s COVID-19 vaccine (AZD1222 or ChAdOx1 nCoV-19) found the average efficacy for two dosing regimens of the vaccine to be 70% in preventing COVID-19. Giving a half dose as the first immunization and a full dose four weeks later resulted in 90% efficacy (n=2,741), while giving a full dose at both immunizations resulted in 62% efficacy (n=8,895). No safety issues were found.
7. An analysis of data from four AZ trials (NCT04324606, NCT04400838, NCT04444674, ISRCTN89951424) included 17,177 patients, with 332 developing COVID-19. The analysis found overall efficacy to be 66.7% two weeks or more after the second dose. Vaccine efficacy was 63.1% in patients that received two full doses of the vaccine and 80.7% in patients that received a half dose initially, followed by a full dose for the booster. Exploratory endpoints included efficacy with different dosing intervals. Patients that received a second dose of vaccine at 12-weeks or later had antibody titers 2-fold higher with 81.3% efficacy. Efficacy was 55.1% in patients whose interval between doses was less than six weeks. A single dose of the vaccine demonstrated efficacy of 76% for 90 days in the prevention of symptomatic infection but did not offer protection for asymptomatic infection. 
8. In an 8,534 patient, Phase III trial (NCT04400838), 520 patients developed COVID-19. The virus was sequenced in 301 patients. Efficacy in preventing symptomatic infection with the AstraZeneca COVID-19 vaccine was 70.4% against the B.1.1.7 (U.K.) variant and 81.5% against the original SARS-CoV-2 viruses. The vaccine was less efficacious for asymptomatic infection with 28.9% efficacy for B.1.1.7 compared to 69.7% for original viruses.
9. In a 2,026 patient, South-African, Phase I/II trial (NCT04444674), 2.5% of patients that received the AstraZeneca COVID-19 vaccine became infected with COVID-19 compared to 3.2% with placebo for a vaccine efficacy of 21.9% in HIV negative adults. 92.9% of COVID-19 infections were caused by the B.1.351 (South African) variant. Vaccine efficacy against the B.1.351 variant was 10.4%. The researchers also tested antibodies from 25 patients and found that vaccine recipients had no neutralization activity against the B.1.351 variant.
10. A review of outcomes in British patients over 70, found vaccine effectiveness after one dose, at 28 to 34 days, to be 61% with the Pfizer-BioNTech vaccine and 60% with the or Astra Zeneca vaccine. The vaccines provided an approximately 80% protection against hospital admission. Effectiveness after a second dose of the Pfizer-BioNTech vaccine was estimated at 90% in patients 80 and older. No estimate was provided for effectiveness after a second dose of the Astra Zeneca vaccine.
11. AstraZeneca is designing a new trial to evaluate the efficacy of the half-strength initial dose/full strength second dose regimen that demonstrated 90% efficacy in a small subpopulation in a 22,690, Phase III trial.  
12. The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) has issued an emergency authorization for AstraZeneca’s COVID-19 vaccine. 
13. In a 32,449 patient, Phase III, trial (NCT04516746), two doses of AstraZeneca’s COVID-19 vaccine, given 4-weeks apart, had efficacy of 74% overall and 83.5% in patients 65 years and older. Efficacy was defined as prevention of symptomatic COVID-19.

• The DSMB notified NIAID and BARDA that initial announcement by AZ on 3/22/2021 may have included outdated information that gave an incomplete view of efficacy. AZ based the announcement on an interim analysis with a data cutoff of 2/17/2021. AZ promised to provide an update within 48 hours. In the early announcement, AZ announced efficacy of 79% with 100% efficacy at preventing severe disease and hospitalizations. Efficacy was calculated after 141 cases of COVID-19.
• AstraZeneca paused all clinical trials for its COVID-19 vaccine (AZD1222), on 9/6/2020, due an adverse event in one patient. The patient suffered neurological symptoms consistent with transverse myelitis. The UK Medicines Health Regulatory Authority investigated the occurrence as a potential safety problem and allowed the trial to continue on 9/12/2020. The FDA allowed the Phase III trial for AstraZeneca’s coronavirus vaccine, AZD1222, to resume in the US, on 10/23/2020 after an FDA review of all safety data concluded the vaccine was safe.
• A preprint article describes the immunity response in 165 patients, 80 or older, that received a single dose of either the Pfizer-BioNTech or Astra Zeneca vaccine. Antibodies were elicited in most patients (93% and 87%). Previous infection caused a higher antibody response.
• Researchers in Scotland examined COVID-19 cases and found the Delta variant as the dominant variant in the country. The researchers estimated the effectiveness of the Pfizer-BioNTech COVID-19 vaccine to be 92% for the Alpha variant and 73% for the Delta variant. The Astra Zeneca COVID-19 vaccine was 73% effective for the Alpha variant and 60% effective for the Delta variant.
• A 19,109 patient, British observational study described the effectiveness of COVID-19 vaccines against the Alpha and Delta variant. After two doses, the effectives of the Pfizer-BioNTech COVID-19 vaccine was estimated to be 93.7% for the alpha variant and 88% for the delta variant. The effectiveness of the AstraZeneca vaccine was estimated to be 74.5% for the alpha variant and 67% for the delta variant.
• A preprint draft provides results from a study examining antibody levels after a delayed second dose or third dose of the AstraZeneca COVID-19 vaccine. Antibody titers were higher with longer intervals. A third dose of the vaccine produced higher antibody titers and T-cell response.

Some countries have expressed concern for an increased risk for thromboembolic events with the AstraZeneca COVID-19 vaccine.

• The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) found the AstraZeneca COVID-19 vaccine causes a rare adverse event of thrombosis in combination with thrombocytopenia. PRAC reviewed 62 cases of cerebral venous sinus thrombosis and 24 cases of splanchnic vein thrombosis and concluded the thrombi are most likely to occur within the first two weeks after administration in women younger than 60. PRAC advises the benefits of the vaccine continue to outweigh the risks and the vaccine is effective at preventing COVID-19 and reducing hospitalizations and deaths.
• The U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) has recommended that while prompt vaccination with the AZ vaccine outweigh the risk of thrombosis, patients under 30 should be offered an alternative vaccine.
• The World Health Organization has stated that a causal relationship between the rare event of thrombosis in combination with thrombocytopenia had not been proven, but surveillance and investigation should be continued. 
• German researchers found evidence the rare immune thrombotic thrombocytopenia is mediated by platelet-activated PF4 antibodies that is clinically similar to autoimmune heparin-induced thrombocytopenia. Norwegian researchers found similar evidence in a separate group of patients.
• An analysis of data from 21,583 participants in the U.S. AZ vaccine trial did not find an increased risk of thromboembolic events.
• A retrospective analysis of 513,284 patients, found the incidence of cerebral venous thrombosis to be eight times more common in patients that developed COVID-19 that in patients that received the AstraZeneca vaccine and ten times more common than in patients that received the Pfizer-BioNTech or Moderna vaccine.
• A report describes 23 patients with thrombosis and thrombocytopenia 6 to 24 days after receiving the first dose of the AstraZeneca COVID-19 vaccine. As in previous descriptions the patients were positive for antibodies to platelet factor 4 (PF4), unrelated to the use of heparin. The researchers recommend avoiding heparin and platelet transfusions, using a nonheparin anticoagulant and intravenous immune globulin considered. An algorithm is provided for testing and treating patients. 
• A retrospective analysis of 513,284 patients, found the incidence of cerebral venous thrombosis to be eight times more common in patients that developed COVID-19 than in patients that received the AstraZeneca vaccine and ten times more common than in patients that received the Pfizer-BioNTech or Moderna vaccine.
• British researchers analyzed the national British health database and found a higher incidence and prolonged duration for thrombocytopenia, venous thromboembolism and arterial thromboembolism leading to hospital admission or death in more people infected with COVID-19 than who received at least one vaccination with either the AstraZeneca or Pfizer-BioNTech vaccines.
• In its COVID-19 vaccination recommendations, the CDC includes patients that have received the complete vaccination series with the AstraZeneca vaccine or the Novavax vaccine as being fully vaccinated and they do not also need immunization with a vaccine that is approved or available under an EUA.

BioNTech – is developing a messenger RNA (mRNA) vaccine (BNT162) in partnership with Pfizer and Fosun Pharma. BioNTech will manufacture the vaccine in Germany and Pfizer will manufacture the vaccine at three sites in the US and one in Belgium. Pfizer is not relying on government funding for development and says it can move faster with self-funding. HHS and the BARDA awarded Pfizer and BioNTech $1.95 billion for the first 100 million doses of their experimental COVID-19 vaccine as part of operation Warp Speed. The U.S. government also has an option for an additional 500 million doses. Pfizer plans to price the two dose COVID-19 vaccine regimen at a minimum of $19.50 per dose or $39 for the two dose course of immunizations for the additional 500 million doses the U.S. can purchase under an Agreement. The price will be the same for other developed countries that make the same volume commitment. 

1. Two doses of BNT162 are given 21 days apart.
2. The FDA approved Pfizer-BioNTech COVID-19 Vaccine, on 8/23/2021, for the prevention of COVID-19 disease in individuals 16 years of age and older. The vaccine will now be marketed as Comirnaty (koe-mir’-na-tee).  Comirnaty will continue to be available through an EUA for individuals 12 to 15 years. The EUA also covers a booster dose for immunocompromised patients.
3. ACIP recommends the use of the Pfizer-BioNtech COVID-19 vaccine (Comirnaty) in people 12 and older.
4. The FDA amended the EUAs for both mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna) to allow for the use of a third dose in certain immunocompromised individuals.
5. On 9/22/2021, the FDA amended the EUA for the Pfizer-BioNTech COVID-19 Vaccine to allow a booster dose, given at least six months after completion of the second dose to patients 65 years and older or who are at high risk for severe COVID-19, which includes healthcare professionals, frontline workers and people that live in group settings. On 9/23/2021, ACIP recommended a booster dose of the Pfizer-BioNTech vaccine for patients 65 years and older, residents of long-term care facilities and 50 to 64 years patients at high risk for severe COVID-19. Patients who at 18 to 49 at high risk for severe COVID-19 infection may receive one, if the patient wants one. ACIP did not recommend a booster dose for health care professionals, other front-line workers or people that live in group settings. The CDC agreed with ACIP on recommending a booster dose for patients 65 years and older, residents of long-term care facilities and patients at high risk for severe COVID-19, but also added a recommendation for health care professionals, other front-line workers or people that live in group settings. 
6. The FDA and AAP are warning physicians and parents not to vaccinate children under 11 years with the adult vaccine. Much smaller dosages are being used in clinical trials and not enough clinical evidence is currently available to predict the correct dose. Pfizer expects to have pediatric data available beginning in September. Trial results will be released for ages 5 to 11, then 2 to 5 and finally 6 months to 2 years in October or November. Once pediatric data is available Pfizer and BioNTech will request an EUA. 
7. An FDA review of clinical data for Pfizer and BioNTech’s COVID-19 vaccine found evidence supported 95% efficacy and no major safety concerns. On 12/10.2020, the FDA’s Vaccines and Related Biological Products Advisory Committee voted 17 to 4, with one abstention to recommend an emergency use authorization for BNT162b2 as prophylaxis for COVID-19 infections for patients 16 years and older. Pfizer and BioNTech will monitor for anaphylactic reactions as part of their pharmacovigilance plan after two patients in the U.K. developed reactions after receiving the vaccine.
8. In the Pfizer funded, 43,0448 patient, Phase II/III trial (NCT04368728) BNT162b2 was administered as two 30 mcg immunizations given 21-days apart. BNT162b2 efficacy was found to be 95% (8 cases of COVID-19 vs 162 cases), 28 days after the first dose and 7 days after the second dose. Protection for COVID-19, began around 12 days after the first dose, with 52% efficacy between the first and second doses. Efficacy was consistent across age, gender, race and ethnicity demographics. The most common ADR were mild-to-moderate pain at the injection site, fatigue, and headache. There were few serious ADR and the incidence was similar to placebo. After the second dose, fever developed in 16% of younger patients and 11% of older patients. 
9. Pfizer and BioNTech provided an update for their COVID-19 vaccine trial (NCT04368728) after 927 symptomatic cases of COVID-19 developed after up to six-months of follow-up for 91.3% efficacy. For prevention of symptomatic infection, the vaccine was 100% effective using CDC criteria and 95.3% effective using FDA criteria. There were 800 patients from South Africa in the trial and nine infections developed, six of which were caused by the B.1.351 (South African) variant. All infections developed in the placebo group, suggesting good efficacy, but based on limited data.
10. In a 2,260 patient, Phase III trial (NCT04368728), no cases of COVID-19 developed in patients immunized with the Pfizer-BioNTech COVID-19 vaccine compared to 16 cases in the placebo group for 100% efficacy in patients 12 to 15.
11. Pfizer and BioNTech announced that in a 2,268 patient, Phase II/III trial (NCT04816643), two 10 mcg doses of their COVID-19 vaccine given 21 days apart, to children 5 to 11 years, produced antibody titers comparable to the levels seen with two 30 mcg adult doses in adolescents and young adults age 16 to 25 years. Data for children 2 to 5 years of age and children 6 months to 2 years of age is forecast to be available in the fourth quarter.
12. In a review of data from 1,736,832 patients from an Israeli managed care database, found the Pfizer/BioNTech COVID-19 vaccine increases the risk for lymphadenopathy, herpes zoster infection and appendicitis, while COVID-19 increases the risk for arrhythmia, acute kidney injury, pulmonary embolism, deep-vein thrombosis, myocardial infarction, pericarditis, and intracranial hemorrhage. While the vaccine increased the risk for myocarditis (2.7 events per 100,000 persons) the risk was over four times higher with COVID-19 (11.0 events per 100,000 persons).
13. A review of outcomes in British patients over 70, found vaccine effectiveness after one dose, at 28 to 34 days, to be 61% with the Pfizer-BioNTech vaccine and 60% with the or Astra Zeneca vaccine. The vaccines provided an approximately 80% protection against hospital admission. Effectiveness after a second dose of the Pfizer-BioNTech vaccine was estimated at 90% in patients 80 and older. No estimate was provided for effectiveness after a second dose of the Astra Zeneca vaccine.
14. CDC researchers analyzed the outcomes in 1,843 health care professionals and found the mRNA vaccines’ efficacy to be 82% in preventing COVID-19 after one dose and 94% after two doses.
15. The CDC analyzed the safety data of the Pfizer-BioNTech or Moderna vaccines after 13,794,904 vaccine doses were given. The incidence of adverse events was 0.05% with the most common being headache, fatigue, and dizziness. Only 9.2% of adverse events were considered serious. The overall rate of anaphylaxis was similar to other vaccines with 4.5 events per million doses.
16. A retrospective analysis by Israeli researchers found the Pfizer-BioNTech vaccine to reduce COVID-19 infection by 30% and symptomatic infections by 47% during the first two weeks after the initial vaccination. In days 15-28 after the immunization, all COVID-19 infections are reduced by 75% and symptomatic infections by 85%.
17. A published retrospective review by Israeli researchers compared the outcomes of 596,618 patients that received the Pfizer-BioNTech COVID-19 vaccine to an equal number of non-vaccinated patients. At one to three weeks after the first immunization, vaccine effectiveness was estimated to be 46% in preventing documented infection, 57% to prevent symptomatic illness, 74% to prevent hospitalization, and 62% to prevent severe disease. Outcomes at seven days and beyond after the second vaccination were 92% in preventing documented infection, 94% to prevent symptomatic illness, 87% to prevent hospitalization, and 92% to prevent severe disease. the Pfizer-BioNTech vaccine was also found to be 90% effective in preventing asymptomatic infection.
18. A preprint draft describes how a single dose of either the Pfizer-BioNTech or Moderna vaccine given to patients that recovered from COVID-19 resulted in high levels of antibodies that were effective in neutralizing the B.1.351 (South African) variant. Without the boost in immunity from the vaccine, the patients’ antibody levels were not robust enough to neutralize the variant.
19. A preprint draft, describes a small trial, where patients that had recovered from COVID-19 had a robust increase in antibody titers after the first dose of the Pfizer-BioNTech vaccine, but a small increase after a second dose. Patients that had not been infected with COVID-19, had a robust increase with both doses.
20. Israeli researchers administered a single dose of the Pfizer-BioNTech COVID-19 vaccine to six patients that had recovered from a COVID-19 infection with the original Wuhan virus. Antibodies taken after recovery, but before vaccination were able to neutralize the original virus and the B.1.1.7 (U.K.) and P.1 (Brazil) variants, but not the B.1.351 (South African) variant. After vaccination, antibody titers were greatly increased and neutralized all strains of the virus.
21. The FDA has advised it is acceptable to use each additional full dose in the vials.  But partial doses from different vials, should not be combined for a full dose, since the vials are preservative free.
22. Pfizer and BioNtech are receiving help in manufacturing their vaccine. Sanofi agreed to manufacture 125 million doses in a German plant for use in European countries and Novartis has agreed to fill vaccine vials at a Swiss plant.
23. In an unpublished and unedited report, researchers describe how antibodies in serum from 20 people, who had received two doses of the Pfizer-BioNTech COVID-19 vaccine, neutralized SARS-CoV-2 with and without the N501Y mutation with similar efficacy. The N501Y mutation has been identified as causing a faster spread of the disease in the U.K. It has also been identified in the U.S. N501Y is one of a series of mutations found in the B.1.1.7 lineage spike protein. In a second unpublished and unedited report, researchers describe how antibodies in serum from 16 people, who had received two doses of the Pfizer-BioNTech COVID-19 vaccine, neutralized SARS-CoV-2 pseudoviruses with the B.1.1.7 variant spike protein as well as it did the Wuhan reference strain.
24. Researchers from Pfizer, BioNTech and the University of Texas tested antibodies from the Pfizer-BioNTech COVID-19 vaccine against the new COVID-19 variants, B.1.526, B.1.429, and B.1.1.7+E484K. In the lab tests the antibodies were able to neutralize all three variants.
25. An unpublished and unedited study compared the increase in antibodies for SARS-CoV-2 in seropositive COVID-19 patients to uninfected volunteers. Seropositive patients developed antibody titers that were ten times higher after one dose of Moderna’s or Pfizer’s vaccine compared to the antibody levels attained by the volunteers after two doses. The seropositive patients also had a higher incidence of adverse effects. 
26. Pfizer and BioNTech are evaluating the effects of a third vaccination (second booster vaccination), 6 to 12 months after the patients received the first of two doses in a Phase I trial. The goal of the study is to determine if boosting antibody titers will be enough to prevent infections from new COVID-19 variants. The companies are also discussing the design of a study to evaluate a variant-specific vaccine with the FDA and EU.
27. The FDA approved a change to the storage and transportation requirements for the Pfizer-BioNTech COVID-19 Vaccine. The vaccine can now be transported and stored at conventional freezer temperatures for up to two weeks. There is no change to the requirements for thawed or diluted vials. Thawed vials, before dilution, can still be stored at refrigerator temperatures for up to 5 days. Diluted vials can be held at refrigerator temperature or room temperature for up to 6 hours.
28. Researchers estimate the incidence of anaphylaxis with the Pfizer-BioNTech COVID-19 vaccine as 11.1 cases per million doses administered.
29. In a preprint draft of a 108,851 patient, British trial, efficacy in preventing COVID-19 was 60-70% after one dose of the Pfizer-BioNTech vaccine and 85-90% after two doses. The AstraZeneca COVID-19 vaccine was 60-73% efficacious after one dose. Data was not available to determine efficacy after two doses of the AZ vaccine. Both vaccines were effective in reducing hospitalizations. 
30. Researchers at the Icahn School of Medicine compared the antibody response to the Pfizer-BioNTech and Moderna COVID-19 vaccines in 43 recovered COVID-19 patients to 67 healthy volunteers. The seronegative patients had a low, but variable response after the first vaccination, while the seropositive patients had antibody titers that were 10 to 45 times higher. After the second dose there was a three-fold increase in healthy patients, but no increase in recovered patients.
31. A retrospective analysis of 513,284 patients, found the incidence of cerebral venous thrombosis to be eight times more common in patients that developed COVID-19 that in patients that received the AstraZeneca vaccine and ten times more common than in patients that received the Pfizer-BioNTech or Moderna vaccine.
32. An analysis of patients with immune-mediated inflammatory diseases who were receiving immunomodulatory treatments found that use of methotrexate decreased the immune response from the Pfizer-BioNTech COVID-19 vaccine. Over 90% of patients that were receiving a TNF blocker achieved a robust antibody response compared to only 62.2% of patients that were receiving methotrexate that achieved an adequate response.
33. In the 23,324 patient, SIREN trial, the Pfizer-BioNTech COVID-19 vaccine was 70% effective 21 days after the first dose and 85% effective seven days after the second dose in British health care professionals. The dominant variant in circulation during the study was the B1.1.7 (U.K.) variant.
34. In Scotland, the second dose of a COVID-19 vaccine is given 12-weeks after the first dose. An analysis of 1,331,993 patients, found the Pfizer-BioNTech COVID-19 vaccine was 91% effective and the AstraZeneca vaccine was 88% effective in preventing hospital admission for COVID-19 28–34 days after vaccination. In patients 80 and older, the vaccines were 88% and 81% effective.
35. Researchers in Qatar estimated the efficacy of the Pfizer–BioNTech COVID-19 vaccine as 89.5% against the B.1.1.7 (U.K.) variant and 75% for the B.1.351 (South Africa) variant. For severe, critical, or fatal disease due to the B.1.1.7 or B.1.351 variants, efficacy was 97.4%. During data collection, 50% of cases were from the B.1.1.7 variant and 44.5% from the B.1.351 variant.
36. Researchers in Scotland examined COVID-19 cases and found the Delta variant as the dominant variant in the country. The researchers estimated the effectiveness of the Pfizer-BioNTech COVID-19 vaccine to be 92% for the Alpha variant and 73% for the Delta variant. The Astra Zeneca COVID-19 vaccine was 73% effective for the Alpha variant and 60% effective for the Delta variant.
37. An analysis of data by Israeli researchers found the effectiveness of the Pfizer-BioNTech COVID-19 vaccine to be 91% to prevent severe disease and 88% to prevent hospitalizations. The vaccine had an estimated effectiveness of 41% to protect against symptomatic disease and 39% to prevent infection due to the Delta variant compared to an estimated 64% effectiveness at the beginning of July.
38. A 19,109 patient, British observational study described the effectiveness of COVID-19 vaccines against the Alpha and Delta variant. After two doses, the effectives of the Pfizer-BioNTech COVID-19 vaccine was estimated to be 93.7% for the alpha variant and 88% for the delta variant. The effectiveness of the AstraZeneca vaccine was estimated to be 74.5% for the alpha variant and 67% for the delta variant.
39. On 5/19/2021, the FDA approved storage of the Pfizer-BioNTech COVID-19 vaccine at refrigerator temperatures for up to 30 days. The EMA recommended extending the storage time for the Pfizer-BioNTech COVID-19 vaccine from five days to 31 days at normal refrigerator temperatures.
40. Pfizer and BioNTech announced results from a Phase I trial (NCT04955626), where patients received a third Pfizer-BioNTech COVID-19 vaccine dose eight to nine months after the second. Antibody titers elicited after the third dose were 5 to 8 times higher for the original COVID-19 virus, 15 to 21 times higher for the Beta variant, 5 times higher in 18 to 55 year-olds for the Delta variant and 11 times higher for 65 to 86 year-olds for the Delta variant.
41. An Israeli study of data from an HMO database found a third dose of the Pfizer-BioNTech COVID-19 vaccine to be 86% effective in people aged over 60.
42. British researchers analyzed the national British health database and found a higher incidence and prolonged duration for thrombocytopenia, venous thromboembolism and arterial thromboembolism leading to hospital admission or death in more people infected with COVID-19 than who received at least one vaccination with either the AstraZeneca or Pfizer-BioNTech vaccines.
43. An analysis of antibody levels in 1,647 Belgium health care workers found higher antibody titers after two doses of the Moderna COVID-19 vaccine compared to the Pfizer-BioNTech vaccine, whether or not the patient had previously been infected with COVID-19. The increase in antibody titers was higher after infection than the difference between the two vaccines. It is unknown if the difference in antibody levels is clinically significant.
44. In a review of data from 1,137,804 patients from the Israeli Ministry of Health database, found that a booster dose of the Pfizer/BioNTech COVID-19 vaccine, given at least five months after the second dose in patients 60 years or older, resulted in a reduction in confirmed and severe cases of COVID-19, during the first 12 days after the third dose.
45. In a six-month follow-up of the pivotal trial for the Pfizer/BioNTech COVID-19 vaccine (NCT04368728), vaccine efficacy was 91.3%.  Vaccine efficacy gradually decreased over time, but efficacy for severe disease remained high at 96.7% and 100% for the Beta variant. Overall efficacy was 84% from month four to six.
46. A third (booster) dose of the Pfizer/BioNTech COVID-19 vaccine was given to the pivotal trial population (NCT04368728), 7.9 to 8.8 months after the second dose. Antibody titers increased after the third dose for the original SARS-CoV-2 strain and variants.
47. A review by the FDA for the Vaccines and Related Biological Products Advisory Committee (VRBPAC) found a third dose of the Pfizer-BioNTech vaccine to be safe and well tolerated. The review questioned whether the available data and quality of the studies support a need for a third (booster) dose of the vaccine, since there is still adequate protection from severe COVID-19 and death.
48. The FDA VRBPAC voted 16 to 2 to recommend approval of a booster dose of the Pfizer-BioNtech COVID-19 vaccine, given 6-months after the second dose, in patients 65 years and older. The committee also voted 18 to 0 to recommend a booster dose for younger patients at high risk for severe COVID-19.
49. A study analyzing the antibody levels produced with the Pfizer-BioNTech and Moderna COVID-19 vaccines, in 167 adults, found the Pfizer-BioNTech elicited lower antibody titers in patients 50 years and older compared to patients less than 50 years. Antibody titers were also lower in age-similar peers compared to Moderna vaccine recipients. There were no differences in antibody levels between older and younger patients that received the Moderna vaccine. This study did not measure neutralizing antibodies. 

CureVac - is developing CVnCoV, an mRNA vaccine formulated with lipid nanoparticles. The Coalition for Epidemic Preparedness Innovations (CEPI) has provided funding to CureVac and Germany invested $337 million in CureVac to support development and manufacture of a COVID-19 vaccine. CureVac has signed an agreement with Bayer to help develop, distribute and market its COVID-19 vaccine candidate CVnCoV.

1. An unpublished report describes interim data from a 248 patient, Phase I dose ranging trial (NCT04449276), where two 12 mcg doses of CureVac’s COVID-19 vaccine, CVnCoV, elicited antibody levels similar to levels seen in a group of recovered COVID-19 patients. In the Phase I trial, healthy patients were randomized to doses of 2, 4, 6, 8 and 12 mcg on days 1 and 29. The 12 mcg dose was chosen for future trials. Most adverse events were mild or moderate. The most common were headache and fatigue, myalgia, chills and fever.
2. CureVac is evaluating CVnCoV in a 700 patient, Phase II dose-ranging trial (NCT04515147) in Peru and Panama.
3. Curevac is evaluating CVnCoV for the prevention of COVID-19 in the 36,500 patient, Phase IIb/III, HERALD trial (NCT04652102) in Europe and Latin America.
4. Curevac is evaluating the safety, reactogenicity and antibody response of CVnCoV in a 2,520 patient, Phase III, trial (NCT04674189) in German adult healthcare providers.
5. GSK will manufacturer up to 100 million doses of CureVac COVID-19 vaccine candidate CVnCoV. GSK and CureVac will also develop a multi-valent vaccine to offer broader protection against COVID-19 mutations. The companies are targeting 2022 for the multi-valent vaccine to be available.
6. Novartis will manufacture for up to 50 million doses of CureVac’s COVID-19 vaccine candidate CVnCoV by the end of 2021 and up to a 200 million more doses in 2022.
7. Curevac announced interim data from the 36,500 patient, Phase IIb/III, HERALD trial (NCT04652102), where the mRNA COVID-19 vaccine CVnCo demonstrated 47% efficacy after 134 cases of COVID-19 developed in the European and Latin American study population. An analysis of COVID-19 cases found all but one infection was from COVID-19 variants.
8. Curevac announced that in the 40,000 patient, Phase IIb/III, HERALD trial (NCT04652102), their mRNA COVID-19 vaccine, CVnCo, demonstrated 48% efficacy after 228 cases of COVID-19 developed in the European and Latin American study population. Efficacy was 53% in patients aged 18 to 60. An analysis of COVID-19 cases found 86% were caused by Variants of Concern or Variants of Interest.

Inovio - is developing a DNA vaccine (INO-4800). Inovio has potential supply issues. The company can only produce 1 million doses by the end of 2020. Inovio has contracted Ology Bioservices and Richter-Helm BioLogics to add manufacturing capacity but is suing VGXI and GeneOne Life Science, its current plasmids suppliers, to transfer the technology to Ology and Richter-Helm.

1. INO-4800 is administered by electroporation, where a small electrical pulse opens small pores in cells to allow the DNA to enter. Two doses are given four weeks apart.
2. Inovio initiated a 40 patient, Phase I trial in April (NCT04336410). Patients received two doses of INO-4800 4-weeks apart. In June, Inovio announced the vaccine elicited antibodies in 94% of patients, 6-weeks after the second immunization, and no safety issues were identified.
3. The FDA placed a hold on a Phase II/III trial evaluating Inovio’s COVID-19 vaccine, INO-4800, due to questions regarding the vaccine and the Cellectra 2000 delivery device  used in the trial.
4. The Federal Government will not fund a Phase III trial of  Inovio’s COVID-19 vaccine, but will continue to fund a Phase II trial. Depending on the results of the trial, Inovio may run a Phase III trial with China’s Advaccine and the International Vaccine Institute outside the U.S.

Johnson and Johnson – is developing a non-replicating viral vector vaccine and will use J&J’s AdVac and PER.C6 technologies developed in the Ebola and HIV vaccine programs to allow rapid upscale production of its COVID-19 vaccine Ad26.COV2-S. J&J forecasts that it will be able to produce 1 billion doses by the beginning of 2021. The Departments of Defense and Health and Human Services, as part of Operation Warp Speed, have awarded Johnson & Johnson $1 billion for the first 100 million doses ($10 per dose) of its experimental COVID-19 vaccine. The supply will be used for clinical trials or provided, at no charge, through a U.S. vaccination program. The U.S. government also has an option for an additional 200 million doses.

1. J&J began development work on a single dose vaccine, Ad26.COV2-S in March 2020.
2. On 2/27/2021 the FDA granted an emergency use authorization (EUA) to Johnson and Johnson’s COVID-19 vaccine for the prevention of COVID-19 for individuals 18 years of age and older. Vaccine Fact Sheets are available for Healthcare Providers and Vaccine Recipients/Caregivers. The CDC's Advisory Committee on Immunization Practices (ACIP) recommend the Johnson & Johnson Covid-19 vaccine on 2/28/2021. The FDA’s Vaccines and Related Biological Products Advisory Committee voted 22 to 0 to recommend an emergency use authorization (EUA) for J&J COVID-19 vaccineas prophylaxis for COVID-19 infections for patients 18 years and older. 
3. An FDA review of Johnson & Johnson's single dose COVID-19 vaccine, found it to be safe and effective, based on data from the 39,321 patient ENSEMBLE study. FDA reviewers confirmed the 66% overall efficacy. The review found the vaccine to be efficacious for all age groups and ethnicities but noted a decrease in efficacy for patients 60 years and older with risk factors. The vaccine was 77% efficacious at two weeks in preventing severe and critical COVID-19 and 85% efficacious at four weeks. J&J’s vaccine was less effective against the South African variant (B.1.351) with efficacy of 52% at four weeks but maintained protection against severe and critical infection with 82% efficacy. In looking at only U.S. trial participants, efficacy was 72%. The most common adverse effects are injection site pain, headache, fatigue and myalgia. J&J's vaccine can be stored at refrigerator temperatures for at least 3 months.
4. On 4/14/2021, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended that a pause in administering the J&J COVID-19 vaccine be continued, to give the committee more time to analyze a more complete data set. ACIP plans to vote within seven to 10 days on a recommendation for vaccine.
5. The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) recommended adding a warning regarding a rare adverse event of thrombosis in combination with thrombocytopenia to the product label for the Johnson & Johnson COVID-19 vaccine. PRAC reviewed eight cases of thrombosis with thrombocytopenia among seven million patients that received the vaccine in the U.S. The committee noted that all cases happened within 3 weeks of receiving the vaccine in patients under 60. Most cases occurred in women and were very similar to those seen with the AstraZeneca vaccine.
6. The FDA has added Guillain-Barre syndrome to the Warning section of the Fact Sheet for the Johnson & Johnson COVID-19 vaccine. Most cases occurred within 42 days after vaccination. The occurrence is very low at 100 cases per 12.5 million doses.
7. In a 805 patient, Phase I/IIa trial (NCT04436276), JNJ’s COVID-19 vaccine, Ad26.COV2.S, elicited neutralizing antibodies in two cohorts of patients (18-55 and 65 or older). 29 days after the first dose, neutralizing-antibodies were produced in 99% of patients in the younger cohort and 96% of patients in the older cohort. Antibody titers continued to increase at day 57. A higher dose of the vaccine elicited more antibodies than the lower dose. Some patients received a second dose of the vaccine, which resulted in even higher antibody levels. Longer term data comparing one-dose and two-dose regimens will be reported in the future. The most frequent adverse events were injection site pain, fatigue, headache and myalgia. Adverse events were less common in older patients than younger patients.
8. In the 39,321 patient, Phase III, ENSEMBLE trial (NCT04505722), a single immunization with the J&J COVID-19 vaccine resulted in 66.4% efficacy after 28 or more days after vaccination. The vaccine was 85.4% effective in preventing severe disease. Efficacy was similar across age groups after at least 28 days. In South Africa, efficacy was 64% in South Africa for moderate to severe disease and 81.7% for severe disease. There were eleven cases of venous thromboembolic events in the vaccine group compared to three the placebo group. Only one case of transverse sinus thrombosis with cerebral hemorrhage was seen in in the vaccine group.
9. J&J announced that in the 31,836 patient, Phase III, ENSEMBLE 2 trial (NCT04614948), a booster dose of the J&J COVID-19 vaccine given 56 days after the initial immunization produced vaccine effectiveness of 100% against severe/critical COVID-19, 75% against symptomatic infections globally and 94% in the U.S. 
10. On 4/23/2021, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended lifting the pause on administering the J&J COVID-19 vaccine that was implemented on 4/4/2021. The pause was established to investigate the occurrence of eight cases of thrombosis with thrombocytopenia among seven million patients that received the vaccine in the U.S. On 4/22/2021, ACIP voted 10-4 to resume immunization with the vaccine. The committee also recommended that a warning about the risks of thrombosis with thrombocytopenia syndrome be added to the vaccine information and that clinicians follow the recommendation from the American Society of Hematology guidance for diagnosis and treatment of the condition. The CDC and FDA recommended lifting the pause in immunizations with the J&J vaccine on 4/23/2021. The FDA revised the vaccine EUA, healthcare professional fact sheet and patient fact sheet to include information on thrombosis-thrombocytopenia syndrome (TTS). On 5/12/2021, the CDC announced it had identified 28 cases of thrombosis with thrombocytopenia among 8.7 million patients that received the J&J COVID-19 vaccine and considers the relationship between the vaccine and the adverse event to be a "plausible causal association"
11. Researchers from Johnson & Johnson and academia evaluated the efficacy of antibodies from 25 participants in a Phase I/IIa trial of J&J’s Ad26.COV2-S COVID-19 vaccine (NCT04436276) to neutralize COVID-19 variants. While there were decreased neutralization activity, functional activity was maintained for the Alpha variant, Gamma variant and Beta variant.
12. The Federal Government contracted Emergent Biosolution to manufacturer the active ingredients for COVID-19 vaccines from J&J and AstraZeneca. In March, Emergent had to destroy millions of doses of the J&J vaccine, due to cross-contamination. An FDA inspection has revealed numerous manufacturing, sterility and training issues. Johnson & Johnson has now taken over responsibility for manufacturing their vaccine at the Emergent plant. Production of the AZ vaccine will be moved to a different facility.
13. The FDA extended the shelf life of the Johnson & Johnson COVID-19 vaccine from 3-months to 4.5 months at refrigeration temperature (2-8 C).
14. J&J announced that in the 31,836 patient, Phase III, ENSEMBLE 2 trial (NCT04614948), a booster dose of the J&J COVID-19 vaccine given 56 days after the initial immunization produced vaccine effectiveness of 100% against severe/critical COVID-19, 75% against symptomatic infections globally and 94% in the U.S.
15. Johnson & Johnson announced interim data from two Phase I/IIa trials (1,085 patient, NCT04436276 trial and 1,210 patient, NCT04535453 trial) that suggested a booster dose of its COVID-19 vaccine, Ad26.COV2.S, would boost antibodies titers nine-fold higher.
16. A pre-publication draft of a retrospective review of data from 1,914,670 patients in an insurance claims database estimated the vaccine effectiveness, for the J&J COVID-19 vaccine in states with high Delta variant incidence, at 78% for infections and 85% to prevent hospitalizations.
17. A pre-publication draft of a retrospective review of data from 1,914,670 patients in an insurance claims database estimated the vaccine effectiveness, for the J&J COVID-19 vaccine in states with high Delta variant incidence, at 78% for infections and 85% to prevent hospitalizations.

Medicago - is developing a virus-like particle vaccine (CoVLP). The virus-like particles are created in genetically modified plant cells. Medicago has signed an agreement to provide 76 million doses to Canada.

1. Two doses of CoVLP are given with GSK’s vaccine adjuvant 21 days apart.
2. In an unpublished report of a 180 patient, Phase I, dose-ranging trial, all patients given CoVLP with GSK’s adjuvant elicited neutralizing antibodies after a second dose of the vaccine. Based on results, the lowest dose (3.75 mcg) was chosen for a Phase III trial.
3. A pre-publication draft describes interim results from a 588 patients enrolled in the Phase II portion of a Phase II/III trial (NCT04636697), where the Medicago COVID-19 vaccine (CoVLP) with GSK’s AS03 vaccine adjuvant elicited antibody titers after a second dose in all adult age groups that were ten times higher than a panel of recovered COVID-19 patients

Moderna – is developing the messenger RNA (mRNA) vaccine mRNA-1273. NIH and the Coalition for Epidemic Preparedness Innovations (CEPI) are providing funding to Moderna to develop the vaccine. Moderna hopes to file a BLA for mRNA-1273 in early 2021. Moderna has entered an agreement with Swiss pharmaceutical company Lonzo to help manufacture mRNA-1273. Lonzo will begin manufacturing the vaccine this summer at a U.S. facility and will expand manufacturing to other locations in order to scale up production. Moderna forecasts that 500,000 doses will be available by the end of 2020 and up to 1 billion doses in 2021. Moderna signed an agreement with Catalent to increase capacity for filling vials and packaging doses. Moderna has signed some early vaccine supply deals, pricing their COVID-19 vaccine at $32 to $37 per dose or $64 to $74 per two dose regimen. These early deals were for smaller supplies, so larger orders could have a lower cost per dose, but Moderna has not specified the price. HHS and the BARDA awarded Moderna $1.5 billion for the first 100 million doses ($15 per dose) of its experimental COVID-19 vaccine, mRNA-1273, as part of operation Warp Speed. The U.S. has an option to acquire additional 400 million doses. Should the vaccine be approved, the Federal supply will be provided at no charge, but health care providers can charge for administration. The $1.5 billion is in addition to the $955 million provided to Moderna for vaccine development and manufacturing scale-up.

1. The vaccine is given as two Intramuscular Injection given 28 days apart.
2. An FDA review of clinical data for Moderna’s COVID-19 vaccine found evidence supporting 94.1% efficacy and no major safety concerns. An age specific breakdown of efficacy found the vaccine to be 95.6% efficacious in patients under 65 and 84.6% efficacious in those 65 and older. Efficacy was consistent across race and ethnicity demographics. The most common ADR were mild-to-moderate pain at the injection site, fatigue, headache, muscle pain, joint pain and chills. Three vaccine recipients and one placebo recipient experienced Bell’s palsy, so the FDA has recommended ongoing monitoring for Bell's once widespread vaccination begins. On 12/17/2020, the FDA’s Vaccines and Related Biological Products Advisory Committee voted 20-0, with one abstention to recommend an emergency use authorization for mRNA-1273 as prophylaxis for COVID-19 infections for patients 18 years and older. On 12/18/2020, the FDA granted an Emergency Use Authorization (EUA) for Moderna’s COVID‐19 Vaccine for the prevention of COVID-19 for individuals 18 years of age and older. Vaccine Fact Sheets are available for Healthcare Providers and Vaccine Recipients/Caregivers. The CDC's Advisory Committee on Immunization Practices (ACIP) voted 11-0, with three recusals to recommend use of Moderna’s vaccine on 12/19/2020. The FDA approved use of any full extra doses contained in the vials of the Moderna COVID-19 vaccine.  Because the vaccine does not contain preservative, the FDA advises not to pool excess vaccine from multiple vials to create one dose. The FDA amended the EUAs for both mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna) to allow for the use of a third dose in certain immunocompromised individuals.
3. In the NIAID funded, 30,420 patient, Phase III, COVE trial (NCT04470427), mRNA-1273 administered as two 100 mcg immunizations given 28 days apart resulted in 94.1% efficacy based on 196 cases of COVID-19 that developed in the study population. 24.8% of the study population was over the age of 65 and 16.7% were under 65 with increased risk for severe COVID-19 due to co-morbidities. The study population also included 10.2% who identified as Black or African American and 20.5% Hispanic or Latino. The most common adverse effects were injection site pain, fatigue, myalgia, arthralgia, headache, and erythema/redness at the injection site. There was a slight increase in frequency and severity of adverse effects after the second immunization. ​Moderna provided an update for the COVE trial (NCT04470427), after over 900 symptomatic cases of COVID-19 developed up to six-months of follow-up the vaccine had over 90% efficacy and greater than 95% efficacy in preventing severe infection.
4. In the 3,732 patient, Phase II/III TeenCOVE trial (NCT04649151), no cases of COVID-19 were reported among adolescents ages 12 to 17 years that received two doses of the Moderna COVID-19 vaccine compared to four cases in the placebo group in the adult Phase III COVE study. Efficacy was 93% when measured 14 days after the first dose. The vaccine was well tolerated with no serious adverse events.
5. Moderna announced that mRNA-1273 is stable for 30 days at 2 to 8 C and for six-months at -20 C. This will make the vaccine easier to ship and use in pharmacies, clinics and small hospitals.
6. Moderna completed enrollment in a 600 patient, Phase II trial (NCT04405076) in early July. Patients were given a low dose (50 micrograms), high dose (100 micrograms) or placebo. Half of the patients enrolled in the trial are older than 55. 
7. The CDC estimates the incidence of anaphylaxis with Moderna’s vaccine to be 2.5 cases per million doses administered. 
8. Researches from Moderna and National Institute of Allergy and Infectious Diseases evaluated the ability of COVID-19 antibodies from participants in a Phase I mRNA-1273 trial (NCT04283461), to neutralize pseudoviruses designed to mimic the original virus, the B.1.1.7 (U.K.) variant and the B.1.351 (South Africa) variant. There was no decrease in neutralization of the B.1.1.7 lineage compared to neutralization of the original SARS-CoV-2 virus, but a decrease was seen with the B.1.351 lineage. The researchers concluded that it was unknown how this reduction would affect immunity.
9. The CDC analyzed the safety data of the Pfizer-BioNTech or Moderna vaccines after 13,794,904 vaccine doses were given. The incidence of adverse events was 0.05% with the most common being headache, fatigue, and dizziness. Only 9.2% of adverse events were considered serious. The overall rate of anaphylaxis was similar to other vaccines with 4.5 events per million doses.
10. Moderna is evaluating a second booster dose (three total doses) of its COVID-19 vaccine to boost antibody levels. The company is also developing a vaccine that elicits immunity to the variants. While with the B.1.1.7 variant has been identified in 50 countries and 20 U.S. states, the B.1.351 spike variant has been identified in South Africa.
11. An unpublished and unedited study compared the increase in antibodies for SARS-CoV-2 in seropositive COVID-19 patients to uninfected volunteers. Seropositive patients developed antibody titers that were ten times higher after one dose of Moderna’s or Pfizer’s vaccine compared to the antibody levels attained by the volunteers after two doses. The seropositive patients also had a higher incidence of adverse effects. 
12. Physicians at Massachusetts General Hospital describe delayed cutaneous reactions in 12 patients, who were given the Moderna COVID-19 vaccine. The reactions happened around eight days after the initial immunization and lasted about six days. All patients received their second dose of vaccine and six of the patients developed a second reaction within two days. While the cutaneous reaction is rare, it is more likely to be seen during a mass vaccination campaign, due to the large number of vaccinations.
13. Researchers at the Icahn School of Medicine compared the antibody response to the Pfizer-BioNTech and Moderna COVID-19 vaccines in 43 recovered COVID-19 patients to 67 healthy volunteers. The seronegative patients had a low, but variable response after the first vaccination, while the seropositive patients had antibody titers that were 10 to 45 times higher. After the second dose there was a three-fold increase in healthy patients, but no increase in recovered patients.
14. Researchers tested serum samples from 20 acutely ill COVID-19 patients, 20 recovered patients and 14 patients that had received the Moderna COVID-19 vaccine. All samples demonstrated an ability to neutralize the B.1.1.7 (British) variant.
15. Researchers from NIAID, Emory University, Moderna and others report that antibody titers remained high in 33 patients 200 days after receiving the second Moderna COVID-19 vaccine.
16. Researchers from two vaccine manufacturers, Duke University and NIAID tested the neutralizing activity of antibodies from 14 recovered patients, 26 patients that received the Moderna COVID-19 vaccine and 23 patients that received the experimental Novavax COVID-19 vaccine. The researchers found that while neutralizing activity was modestly lower for the B.1.429 (California) variant, the activity was strong enough to neutralize the variant. The large magnitude of resistance observed with the B.1.351 (South African) variant was cause for concern.
17. Moderna announced that preliminary data from a 40-patient trial suggested that booster injection with either the original Moderna COVID-19 vaccine or a new vaccine targeting the B.1.351 (South African) variant increased antibodies against that variant and the P.1 (Brazil) variant. All participants were previously fully vaccinated with Moderna’s vaccine. The new vaccine is designed to elicit antibodies for the B.1.351 variant eliciting higher titers of antibodies for the variant.
18. In a four-month, 120 patient, Phase IV trial (NCT04885907), 55% of patients that received a third dose of the Moderna COVID-19 vaccine achieved at least 100 U/ml of anti–receptor-binding domain (RBD) compared to 18% that received only two doses in solid organ transplant patients that did not have a previous diagnosis of Covid-19. The percent virus neutralization was 71% in the three-dose group compared to 13% in the two-dose group.
19. A retrospective analysis of 513,284 patients, found the incidence of cerebral venous thrombosis to be eight times more common in patients that developed COVID-19 that in patients that received the AstraZeneca vaccine and ten times more common than in patients that received the Pfizer-BioNTech or Moderna vaccine.
20. CDC researchers analyzed the outcomes in 1,843 health care professionals and found the mRNA vaccines’ efficacy to be 82% in preventing COVID-19 after one dose and 94% after two doses.
21. A retrospective study by Yale identified 16 patients that developed a delayed localized cutaneous reactions 2 to 12 days after receiving the Moderna COVID-19 vaccine. The reaction was near the injection site and was pruritic and painful with edematous pink plaques. The reaction developed in 11 of the patients with the second dose. The reaction was also seen in a small number of patients during the pivotal COVE trial. The reaction had a duration of five days.
22. Moderna is working on pediatric and adolescent studies. The Moderna vaccine has approval for adolescents in Europe.
23. An analysis of antibody levels in 1,647 Belgium health care workers found higher antibody titers after two doses of the Moderna COVID-19 vaccine compared to the Pfizer-BioNTech vaccine, whether or not the patient had previously been infected with COVID-19. The increase in antibody titers was higher after infection than the difference between the two vaccines. It is unknown if the difference in antibody levels is clinically significant.
24. An analysis of antibody levels in 1,647 Belgium health care workers found higher antibody titers after two doses of the Moderna COVID-19 vaccine compared to the Pfizer-BioNTech vaccine, whether or not the patient had previously been infected with COVID-19. The increase in antibody titers was higher after infection than the difference between the two vaccines. It is unknown if the difference in antibody levels is clinically significant.
25. A study analyzing the antibody levels produced with the Pfizer-BioNTech and Moderna COVID-19 vaccines, in 167 adults, found the Pfizer-BioNTech elicited lower antibody titers in patients 50 years and older compared to patients less than 50 years. Antibody titers were also lower in age-similar peers compared to Moderna vaccine recipients. There were no differences in antibody levels between older and younger patients that received the Moderna vaccine. This study did not measure neutralizing antibodies. 

Novavax – is developing a recombinant protein nanoparticle vaccine that will contain coronavirus spike (S) protein antigens and Novavax’s saponin-based Matrix-M adjuvant to enhance immunogenicity. Novax has a $384 million grant from the Coalition for Epidemic Preparedness Innovations (CEPI) and a $60 million grant from the U.S. Department of Defense. Novavax purchased Praha Vaccines and its Czech Republic vaccine factory. That plant has an annual capacity of one billion doses per year. Novavax signed an agreement with Fujifilm Diosynth Biotechnologies to manufacture its COVID-19 vaccine, NVX-CoV2373, in North Carolina and Texas. Novavax also signed contracts with AGC Biologics and PolyPeptide to help produce its Matrix-M adjuvant. In addition Novavax has an agreement with Serum Institute of India to manufacture the antigen component of NVX‑CoV2373. The company now has six antigen production sites and three adjuvant manufacturing sites. This gives Novavax the capacity to produce two billion doses of the NVX-CoV2373 annually beginning in 2021.

1. NVX-CoV2373 is also listed as SARS-CoV-2 rS.
2. The FDA granted Novavax’s COVID-19 vaccine, NVX-CoV2373, a Fast Track Designation for the prevention of COVID-19.
3. Novavax has received $1.6 billion grant from the Departments of Defense and Health and Human Services as part of Operation Warp Speed. The grant will cover the manufacture of 100 million doses of its COVID-19 vaccine, NVX-CoV2373, and a Phase III trial. Dose manufacturing and clinical testing will occur in parallel.
4. Novavax signed an agreement with Fujufilm Diosynth Biotechnologies to manufacture the Novavax COVID-19 vaccine NVX-CoV2373.
5. In a 131 patient, Phase I trial (NCT04368988), the antibody level increased with all doses of Novavax’s NVX-CoV2373 COVID-19 vaccine with or without the Matrix-M adjuvant. Either formulation of the vaccine with adjuvant induced neutralizing antibody levels greater than what is seen in recovered COVID-19 patients. The trial was sponsored by the Coalition for Epidemic Preparedness Innovations and performed in Australia. 
6. In a 14,039 patient, Phase III trial (EudraCT number, 2020-004123-16), two doses of NVX-CoV2373 given 21-days apart resulted in 89.7% efficacy based on 106 cases of moderate to severe COVID-19 that developed in the United Kingdom study population. Five cases of severe disease occurred, and all were in the placebo group. Efficacy was 96.4% against the original COVID-19 strain and 86.3% against the B.1.1.7 (UK) variant. 
7. In a 4,387 patient, Phase IIb trial (NCT04533399), where two doses of the Novavax COVID-19 vaccine given 21-days apart resulted in 49.4% efficacy in a South African population. Most cases of COVID-19 were the B.1.351 (South African) variant. The trial population included medically stable, HIV-positive adults. Efficacy was 60.1% among HIV negative patients. 
8. Novavax announced that in the 29,960 patient, Phase III, PREVENT-19 trial (NCT04611802), NVX-CoV2373, a COVID-19 vaccine from Novavax was administered as two immunizations given 21-days apart. NVX-CoV2373 efficacy was found to be 90.4% (14 cases of COVID-19 vs 63 cases). Efficacy was 91% in patients older than 65 (13% of the population) and younger patients with risk factors. There were no cases of severe disease in the vaccine group and four cases in the placebo group. The diversity of the trial population was shown by 20% being Latin American, 12% African American, 7% native American and 5% Asian American. The most common ADR were mild-to-moderate pain at the injection site, fatigue, headache and muscle pain. There were few serious ADR, and the incidence was similar to placebo. 
9. Novavax has added crossover arms to its studies to allow trial participants that received placebo to get the vaccine without unblinding the trials. A second round of vaccines will be offered for participants in the 15,000 patient, U.K. trial (NCT04583995) and the 30,000 patient, Phase III, PREVENT-19 trial (NCT04611802) in the U.S. and Mexico. Patients that received the vaccine will receive placebo and placebo patients will receive the vaccine. In the 2,905 patient, South African trial (NCT04533399), placebo patients will receive the vaccine, while the original vaccine patients will receive a booster to determine if a booster will improve efficacy for the B.1.351 (South African) variant.
10. Researchers from two vaccine manufacturers, Duke University and NIAID tested the neutralizing activity of antibodies from 14 recovered patients, 26 patients that received the Moderna COVID-19 vaccine and 23 patients that received the experimental Novavax COVID-19 vaccine. The researchers found that while neutralizing activity was modestly lower for the B.1.429 (California) variant, the activity was strong enough to neutralize the variant. The large magnitude of resistance observed with the B.1.351 (South African) variant was cause for concern.
11. Novavax announced preliminary data demonstrating that a single booster dose of NVX-CoV2373, given six months after the initial two-dose regimen resulted in a 4.6-fold increase in antibody titers.
12. Novavax will delay requesting an EUA until October 2021 to complete FDA requirements for its manufacturing process. Novavax plans to seek approval in September 2021 in the U.K., Canada and Australia. The company has already sought approval in India, Indonesia and the Philippines.
13. In its COVID-19 vaccination recommendations, the CDC includes patients that have received the complete vaccination series with the AstraZeneca vaccine or the Novavax vaccine as being fully vaccinated and they do not also need immunization with a vaccine that is approved or available under an EUA.

Sanofi and GSK – Sanofi and GlaxoSmithKline have agreed to work together to develop a vaccine for COVID-19. The companies will use Sanofi’s S-protein COVID-19 antigen based on the company’s recombinant DNA technology in combination with GSK’s pandemic adjuvant technology. The recombinant DNA platform is the same one used to create the quadrivalent influenza vaccine FluBlok. GSK’s vaccine adjuvant reduces the amount of antigen required for a dose enabling a quicker way to scale up production. Both companies have the capacity to manufacture vaccines on a global scale. Sanofi and GlaxoSmithKline received a $2.1 billion grant from Operation Warp Speed to fund clinical trials, scale up manufacturing, and deliver 100 million doses of their COVID-19 vaccine to the U.S. The deal also includes an option for an additional 500 million doses.

1. Sanofi and GSK announced a delay in their COVID-19 vaccine development program when an interim analysis of a 441 patient, Phase I/II trial (NCT04537208) found the vaccine to elicit antibodies comparable to convalescent plasma in patients 18 to 49, but the response in older patients was insufficient.
2. Sanofi and GSK announced interim results from a 722 patient, Phase II trial (NCT04762680), where the companies’ COVID-19 vaccine elicited antibody levels comparable to recovered patients following a second dose in all age groups (18 to 95 years old) of patients from the U.S. and Honduras. Based on the interim results from the Phase II trial, Sanofi and GSK are planning to initiate a 35,000 patient Phase III trial with the goal of submitting data for an emergency use authorization (EUA) in 4Q21
3. Sanofi has signed an agreement with Translate Bio for an mRNA vaccine. A Phase I trial is expected to begin by the end of 2020.

Vaxart is developing the non-replicating adenovirus type-5 (Ad5) viral vector DNA virus, VXA-CoV2-1.

1. VXA-CoV2-1 is administered as an oral tablet that can be stored at room temperature.
2. Two doses of the vaccines are given 29-days apart.
3. Vaxart is evaluating the safety and immunogenicity of a high and low dose of VXA-CoV2-1 in a 48-patient Phase I trial (NCT04563702).

Zydus is developing a DNA vaccine (ZyCoV-D)

1. Zydus reported the vaccine was well tolerated in a 7-day review of data in a Phase I trial involving an unspecified number of patients.
2. Zydus initiated a 1,000 patient trial for ZyCoV-D on 8/6/2020