Last reviewed: January 7, 2022
On this page:
- Overview and Mechanism
- Johnson & Johnson/Janssen COVID-19 Vaccine
- Oxford AstraZeneca COVID-19 Vaccine
The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject.
Vectored vaccines utilize either non-pathogenic organisms or plasmids (the vector) (Vrba, November 2020). Genes of a pathogen — most often those coding for proteins that act as antigens — are inserted into the genome of the vector. The vaccine delivers the vector, which infects host cells and then travels to the nucleus; there the genes of the pathogen are expressed, resulting in the creation of the antigen. The antigen is then expressed on the host cell surface, resulting in the induction of an immune response. This is both a cellular (T cell) and humoral (B cell) response.
Vectored vaccines can be replicating or non-replicating:
- Replicating viral vectored vaccines infect cells, resulting in the production of the vaccine antigen. The viral vector is also produced and is then able to infect new cells, which then create more viral antigen.
- Non-replicating (sometimes called “replication incompetent” or “replication deficient”) viral vectored vaccines infect cells, resulting in the production of the vaccine antigen, but the viral vector cannot be reproduced (van Riel, July 2020).
Two viral vectored vaccines have been authorized for emergency use in many countries. AstraZeneca and Oxford University partnered to develop a viral vectored vaccine utilizing a modified replication-deficient chimp adenovirus vector, ChAdOx1. It contains a gene that encodes for the SARS-CoV-2 spike protein. Johnson & Johnson’s Janssen Biotech developed a viral vectored vaccine utilizing a replication incompetent human adenovirus vector, Ad26, containing a gene that encodes for a stabilized variant of the SARS-CoV-2 spike protein (Ad26.COV2.S).
Multiple viral vectored vaccines utilizing poxviruses, adenoviruses and vesicular stomatitis virus are also in clinical trials for human use; the only FDA-approved viral vectored vaccine is the Ebola vaccine, ERVEBO (Vrba, November 2020).
Mechanisms of Viral Vector COVID-19 Vaccines
Q: What are viral vector vaccines and how do they work?
A: Viral vector vaccines utilize viruses to deliver genes that encode vaccine antigens into host cells (Vrba, November 2020). Genes of a pathogen — typically those that code for specific antigens that elicit a protective immune response — are first inserted into the genome of a viral vector. The vector is a virus different from the one the vaccine is targeting (for example, an adenovirus). The vaccine delivers the vector, which infects host cells; DNA virus vectors (like adenoviruses) then travel to the nucleus. In the nucleus, the genes of the pathogen are expressed, resulting in the creation of the antigen. The antigen is then expressed on the host cell surface, resulting in the induction of an immune response.
Viral vector vaccines can be replicating or nonreplicating:
Replicating viral vector vaccines infect cells, resulting in the production of the vaccine antigen. The viral vector is also produced and is then able to infect new cells, which then create more viral antigen. The only currently licensed replication-competent vaccines are the recombinant vesicular stomatitis virus (rVSV)-Zaire Ebola virus vaccine and the live attenuated tetravalent dengue vaccine.
Nonreplicating viral vector vaccines infect cells, resulting in the production of the vaccine antigen, but the viral vector cannot be reproduced (van Riel, July 2020). Several COVID-19 vaccines are based on this technology, including the Johnson & Johnson/Janssen, Oxford-AstraZeneca and Gam-COVID-Vac (Sputnik V) vaccines.
The Johnson & Johnson/Janssen COVID-19 is the only viral vector vaccine currently available in the U.S. under emergency use authorization by FDA. This vaccine uses a human adenovirus, Ad26, as the viral vector, and encodes for a stabilized variant of the SARS-CoV-2 spike protein.
The Oxford-AstraZeneca COVID-19 vaccine is another viral vector vaccine that has been authorized for use in many countries. This vaccine uses a chimpanzee adenovirus (ChAdOx1, which is based on ChAdY25) as the viral vector. It encodes for the spike protein of SARS-CoV-2. Finally, the Gam-COVID-Vac vaccine (Sputnik V), developed by the Gamaleya Research Institute of Epidemiology and Microbiology in Russia, is another viral vector vaccine that uses two human adenovirus vectors, (Ad26 and Ad5), both of which encode for the SARS-CoV-2 spike protein.
Q: Can the viral vector alter cellular DNA?
A: No. The viral vectors used in COVID-19 vaccines do not integrate into the genome or contain the enzymes needed to insert vector DNA into cellular DNA. Once the viral vector DNA has been transcribed, the vector genome is degraded. The viral vectors enter the nucleus where the genome of the vector, including the gene encoding the vaccine antigen(s), are transcribed by host RNA polymerase into mRNA. The mRNA are exported to the nucleus, where they are transcribed into vaccine antigens. The viral vectors used in COVID-19 vaccines are non-replicating — this means they do not possess the machinery to generate more copies of themselves in vivo and they are degraded by the host cell once their genome has been transcribed.
Q: Can the viral vector COVID-19 vaccines be transmitted in vivo?
A: No. The viral vector used in the Oxford-AstraZeneca and Johnson & Johnson/Janssen COVID-19 vaccines are replication incompetent (sometimes called replication deficient). This means they do not replicate within the human body, and there is no possibility for transmission of the viral vector to other individuals.
Both the Johnson & Johnson/Janssen and Oxford-AstraZeneca COVID-19 vaccines have proven to be effective against COVID-19 in studies conducted in a variety of settings among diverse populations using a variety of clinical endpoints.
In post-authorization studies, both the Oxford-AstraZeneca and J&J/Janssen COVID-19 vaccines have been demonstrated to be safe. One safety signal identified in post-authorization surveillance studies of both vaccines is an association with rare blood clotting events with low platelet counts - thrombosis with thrombocytopenia syndrome (TTS) and vaccine-induced thrombotic thrombocytopenia (VITT) - which were not observed in the Phase 3 trials. The American Society of Hematology maintains an up-to-date resource on TTS/VITT that includes a case definition and recommendations regarding diagnostic evaluation and acute management.
Vaccine-induced thrombotic thrombocytopenia
Vaccine-induced thrombotic thrombocytopenia is a syndrome characterized by venous or arterial thrombosis associated with thrombocytopenia and detectable anti-platelet factor 4 antibodies that occurs within 3 weeks after receipt of either the Oxford-AstraZeneca or Johnson & Johnson/Janssen COVID-19 vaccine. The American Society of Hematology has developed a case definition with recommendations for diagnostic evaluation and management of patients with suspected VITT.
In post-authorization surveillance of the Johnson & Johnson/Janssen COVID-19 vaccine, a small number (n=6) of rare thrombotic events — cerebral venous sinus thrombosis — associated with thrombocytopenia were identified among vaccine recipients based on data reported to VAERS. This led to a brief pause in the use of this vaccine on April 13, 2021 and a review of safety data by CDC’s Advisory Committee on Immunization Practices on April 23, 2021. In this review, 15 total cases of thrombosis with thrombocytopenia syndrome were identified, including 12 cases of CVST. All the TTS cases occurred among women, and 13 of 15 were in women aged 18-49 years old. The median age of the case patients was 37 years, and the median interval from vaccination to symptom onset was 8 days (range, 6−15 days) (MacNeil, April 2021). There was one case of CVST with thrombocytopenia in a male during the Phase 3 trial of Ad26.COV2.S (Sadoff, April 2021).
The Oxford-AstraZeneca COVID-19 vaccine has been associated with both arterial and venous thrombotic events. In an analysis of data reported to EudraVigilance (a drug safety reporting system for the European Union), the European Medicines Agency identified 169 cases of CSVT and 53 cases of splanchnic vein thrombosis following receipt of the Oxford-AstraZeneca COVID-19 vaccine (out of more than 34 million doses administered). These thrombotic events occurred concurrently with thrombocytopenia, usually within 2 weeks of receipt of the vaccine, and mostly among women under age 60. Subsequently, three independent case series from Norway (Schultz, April 2021), Germany/Austria (Greinacher, April 2021) and the United Kingdom (Scully, April 2021) described a total of 39 patients (27 women, 12 men) with venous thromboses associated with thrombocytopenia that occurred within 4 weeks (range 5-24 days) after vaccination with the Oxford-AstraZeneca COVID-19 vaccine. Given the resemblance of this syndrome to heparin-induced thrombocytopenia, in two of these studies the investigators tested case patients for anti-platelet factor 4 antibodies and found elevated titers in the majority of patients, leading them to propose a new syndrome called vaccine-induced thrombotic thrombocytopenia.
J&J/Janssen’s COVID-19 vaccine Ad26.COV2.S is an adenovirus vectored vaccine that has been shown to be highly effective in preventing symptomatic COVID-19 disease.
In April 2021, CDC and FDA lifted a 10-day pause in U.S. use of the J&J/Janssen vaccine prompted by reports of a rare and severe type of blood clot combined with low blood platelet levels after vaccine administration. The agencies’ investigations determined that “available data show that the vaccine’s known and potential benefits outweigh its known and potential risks.” A warning was added to the vaccine’s label reflecting the identification of 15 cases of thrombosis-thrombocytopenia syndrome following administration, all of which occurred in women between the ages of 18 and 59.
FDA's updated fact sheet for providers refers clinicians to the American Society of Hematology’s FAQ on Vaccine-Induced Immune Thrombotic Thrombocytopenia for relevant diagnosis and treatment considerations. Health care providers are asked to report adverse events using VAERS.
Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine Against Covid-19 (Sadoff, April 2021)
Overall, in this interim analysis of a Phase 3 randomized, stratified, double-blind, placebo-controlled trial, Ad26.COV2.S was effective at preventing symptomatic COVID-19 disease and was safe at a median time to follow up of 8 weeks.
- Ad26.COV2.S is a replication-incompetent adenovirus type 26 (Ad26) vectored vaccine encoding a stabilized variant of the SARS-CoV-2 S protein that is given as 1 intramuscular dose.
- In a Phase 3 randomized, stratified, double-blind, placebo-controlled trial of the single-dose Ad26.COV2.S vaccine, 44,325 participants over 18 years of age from 8 countries (United States, South Africa, Brazil, Chile, Argentina, Colombia, Peru, Mexico) underwent 1:1 randomization.
- 43,783 received an injection.
- 21,895 received Ad26.COV2.S and 21,888 received a saline placebo.
- 66.5% (N=29,111) of the study population included in the efficacy analysis was composed of patients 18-59 years of age, whereas 33.5% (N=14,672) of the study population was >=60 years of age.
- 40.8% (N=17,858) had at least 1 comorbidity associated with an elevated risk for progression to severe COVID-19.
- Comorbidities considered to be associated with an elevated risk for severe disease included: obesity, hypertension, type 2 diabetes mellitus, serious heart condition, asthma, HIV infection, COPD, liver disease, cancer, immunocompromised from blood transplant or neurologic conditions.
- Patients included in the per-protocol efficacy analysis had a negative SARS-CoV-2-status at baseline (with a negative RT-PCR and negative serology against the SARS-CoV-2 nucleocapsid at day 1).
- 9.6% of study participants had serologic evidence of prior COVID-19.
- Participants were excluded if they were pregnant, breastfeeding or under age 18.
- Primary efficacy endpoint: The reduction in incidence of moderate to severe/critical COVID-19 among participants without evidence of SARS-CoV-2 infection before the first dose of vaccine in the periods starting 14 days after vaccination and 28 days after vaccination on day 1.
- Moderate COVID-19 was defined as:
- Any 1 of the following new or worsening signs or symptoms: respiratory rate >=20 breaths/minute, abnormal oxygen saturation (SpO2) but still >93% on room air at sea level, clinical or radiologic evidence of pneumonia, radiologic evidence of deep venous thrombosis, shortness of breath or difficulty breathing; OR
- Any 2 of the following new or worsening signs or symptoms: fever (T >=38 C or >=100.4 F), heart rate >=90 beats/minute, shaking chills/rigors, sore throat, cough, malaise as evidenced by loss of appetite, fatigue, physical weakness, and/or feeling unwell, headache, myalgia, gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain), new or changing olfactory or taste disorders, red or bruised looking feet or toes; AND
- Respiratory tract (nasal, throat, sputum or saliva) or other sample (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by RT-PCR.
- Severe/critical COVID-19 was defined as:
- Any 1 of the following: clinical signs at rest indicative of severe systemic illness (respiratory rate >=30 breaths/minute, heart rate >=125 beats/minute, SpO2 <=93% on room air at sea level, or PaO2/FiO2 <300 mmHg), respiratory failure (needing high-flow oxygen, non-invasive ventilation, mechanical ventilation or ECMO , evidence of shock (systolic blood pressure <90 mmHg, diastolic blood pressure <60 mmHg or requiring vasopressors), significant acute renal, hepatic or neurologic dysfunction, admission to ICU or death; AND
- Respiratory tract (nasal, throat, sputum or saliva) or other sample (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by RT-PCR.
- Primary safety endpoints: Solicited events, including local reactions and systemic events from day 1 through day 7 after vaccination, and unsolicited adverse events from days 1 to 28 after vaccination. Medically attended adverse events were collected through 6 months after vaccination. Serious adverse events and adverse events leading to study discontinuation are also being collected for the duration of the study.
- Moderate COVID-19 was defined as:
- The full analysis set included 45.0% females and 33.5% individuals ≥60 years of age. The median age in the total group was 52 years.
- 37.9% of participants represented communities of color, with 19.4% of participants being Black or African American, 3.3% Asian and 0.4% American Indian or Alaska Native; 45.3% were Hispanic/Latino.
- At least 1 high-risk condition for severe COVID-19 was present in 40.8% of participants.
- There were no differences in demographics in the vaccines and placebo groups.
- The median time to follow up for the efficacy data in the interim analysis was 58 days (range, 1-124) after vaccination.
- There were 116 cases of COVID-19 disease at least 14 days after vaccination in the Ad26.COV2.S vaccinated group and 348 in the placebo group, with a vaccine efficacy of 66.9% (95% CI, 59.0-73.4).
- There were 66 cases of COVID-19 disease at least 28 days after vaccination in the Ad26.COV2.S vaccinated group and 193 in the placebo group, with a vaccine efficacy of 66.1% (95% CI, 55.0-74.8).
- Subgroup analyses of the primary efficacy endpoint showed similar efficacy across age groups, genders, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19.
- When stratified by age, the vaccine efficacy was 66.1% (95% CI, 53.3- 75.8) for participants 18 to <60 years of age and 66.2% (95% CI 36.7-83.0) for participants ≥60 years of age at least 28 days after vaccination.
- A secondary endpoint of the study is prevention of severe COVID-19 disease. In the per-protocol set, there were 14 cases of severe/critical COVID-19 in the vaccinated group and 60 in the placebo group at least 14 days after vaccination (vaccine efficacy of 76.7%; 95% CI, 54.6-89.1). Similarly, there were 5 cases of severe/critical COVID-19 in the vaccination group and 34 cases in the placebo group at least 28 days after vaccination (vaccine efficacy of 85.4%; 95% CI, 54.2-96.9).
- Another secondary endpoint was prevention of COVID-19 requiring medical intervention There were 31 COVID-19 hospitalizations with onset at least 14 days after vaccination; 2 occurred in the vaccine group, and 29 occurred in the placebo group, for an efficacy of 93.1% (95% CI, 72.7-99.2).
- There were 5 COVID-19 related deaths reported in the study, all among participants in the placebo group.
- Additional analyses were done to assess efficacy against asymptomatic SARS-CoV-2 infection, which was defined as a participant who did not fulfill the criteria for suspected COVID-19 based on signs and symptoms (specified as no symptoms on the day preceding, day of or at any time after the positive PCR test) and has a SARS-CoV-2 positive RT-PCR test result OR develops a positive serology during the study.
- In an interim analysis of day 71 serology results based on 2,650 participants, there were 18 cases of asymptomatic SARS-CoV-2 infection in the vaccinated group and 50 in the placebo group (vaccine efficacy of 65.5%; 95% CI, 39.9-81.1).
- During the conduct of the study, new SARS-CoV-2 variants emerged in participating countries. In subgroup analyses of vaccine efficacy against moderate to severe/critical COVID-19 by country of participation, vaccine efficacy was lower in South Africa (vaccine efficacy of 52.0%; 95% CI, 30.3-67.4) compared to the United States (vaccine efficacy of 74.4%; 95% CI, 65.0-81.6).
- Strain sequencing analyses of COVID-19 cases in the study is being performed, and as of Feb. 12, 2021, 71.7% of cases have been sequenced.
- In the United States, 96.4% of strain sequences were identified as SARS-CoV-2 Wuhan-H1 variant D614G.
- In South Africa, 94.5% of strain sequences were identified as 20H/501Y.V2 variant (B.1.351).
- Safety data at the time of the interim analysis were available for 43,783 participants, with a median of 8 weeks of follow-up after vaccination.
- Data on solicited local and systemic reactions through 7 days after vaccination and unsolicited adverse events through 28 days after vaccination were available from a safety subset of 6,736 participants.
- The most common solicited adverse reactions in the vaccinated group were injection site pain (48.6%), headache (38.9%), fatigue (38.2%), muscle pain (33.2%) and nausea (14.2%).
- These were more common in patients younger than 60 years of age.
- Grade 3 local reactions occurred in 0.7% of participants that received Ad26.COV2.S, compared with 0.2% of those who received placebo. There were no grade 4 local or systemic reactions in either group.
- Only 1 hypersensitivity event was reported in a vaccine recipient.
- No cases of anaphylactic reactions were reported around the time of vaccine administration.
- There were more venous thromboembolic events in the vaccine group (N=11) compared with the placebo group (N=3).
- In the vaccine group, these events included 6 deep venous thromboses (all in males), 4 pulmonary emboli (1 female, 3 males) and 1 transverse venous sinus thrombosis (male)
- To date, complete data on all participants who are more than 2 months out from vaccine are not available.
- The primary efficacy endpoint was clinical disease; asymptomatic infection was not assessed, although additional data utilizing a serologic endpoint is being collected.
- The trial did not include children less than 18 years of age, pregnant or lactating individuals or immunocompromised individuals
- Only a small number of persons living with HIV were included in the trial, therefore definitive conclusions about safety and efficacy specifically in this group cannot be drawn.
- While there was a small group of people with evidence of prior COVID-19 infection at the time of analysis, the number of cases in this group was too small to draw any conclusions about the efficacy of the vaccine in individuals with prior infection; this may change as the trial continues.
- Serial RT-PCR testing was not performed, and so the efficacy of the vaccine in potentially preventing spread of SARS-CoV-2 could not be determined.
Durable Humoral and Cellular Immune Responses 8 Months after Ad26.COV2.S Vaccination (Barouch, September 2021).
This was a longitudinal immunogenicity study of 20 participants who received the Johnson & Johnson/Janssen COVID-19 vaccine. It included data at 8 months from 10 individuals who received a single dose of the vaccine, and data at 6 months from 10 individuals who received two doses of the vaccine (given 2 months apart). The investigators reported antibody and T cell responses, as well as immune responses against SARS-CoV-2 variants of concern. Neutralizing antibodies were detectable in all participants at the end of follow-up, with a reduction in the median neutralizing antibody titer by a factor of 1.8 from peak to end of follow-up. Neutralizing antibodies were also detected against the Alpha, Beta, Gamma, and Delta variants, suggestive of increasing neutralizing breadth by time since vaccination.
Interim Results of a Phase 1–2a Trial of Ad26.COV2.S Covid-19 Vaccine (Sadoff, January 2021): In this Phase 1-2a placebo-controlled trial of Ad26.COV2.S in 805 adults, who were stratified according to age (18-55 years or ≥65 years), participants were assigned in a 1:1:1:1:1 ratio to receive zero, one, or two doses of low-dose (5 x 1010 vp) or high-dose (1 x 1011 vp) vaccine (placebo followed by placebo, low dose followed by low dose, low dose followed by placebo, high dose followed by high dose, high dose followed by placebo) administered 56 days apart. Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, headache, myalgia and pain at the injection site. Such adverse events were dose-dependent. By day 29 after vaccination, 99% or more participants in all treatment arms had seroconverted. Antibody levels as measured by ELISA correlated with those measured by a wild-type virus neutralization assay. Levels of baseline Ad26 neutralizing antibodies did not correlate with SARS-CoV-2 neutralizing antibody levels following vaccination. All CD4+ T cell responses elicited by vaccine were Th1 skewed.
For up-to-date J&J/Janssen COVID-19 vaccine safety considerations, refer to CDC’s Interim Clinical Considerations for Use of COVID-19 Vaccines.
For up-to-date J&J/Janssen COVID-19 vaccine dosing information, refer to CDC’s product information page.
The Oxford-AstraZeneca COVID-19 vaccine (also known as ChAdOx1 nCoV-19 vaccine and AZD1222) is a non-replicating viral vectored vaccine that utilizes a chimpanzee adenovirus.
The vaccine has not yet been granted U.S. emergency use authorization but has received authorizations in several other countries. In February 2021, the World Health Organization added the vaccine to its Emergency Use List.
Single Dose Administration, and the Influence of the Timing of the Booster Dose on Immunogenicity and Efficacy of ChAdOx1 nCoV-19 (AZD1222) Vaccine (Voysey, March 2021).
Overall, in this updated interim analysis of four parallel randomized controlled trials, a low-dose/standard dose regimen of the Oxford-AstraZeneca vaccine had higher efficacy than a standard dose/standard dose series. Vaccine efficacy was higher with a dosing interval of 12 weeks or more, compared to 6 weeks or less. A single standard dose of vaccine provided 76% protection against symptomatic COVID-19 in the first 90 days after vaccination.
- The Oxford-AstraZeneca COVID-19 vaccine (ChAdOx1/AZD1222) is a replication-deficient chimpanzee adenovirus (ChAd) vectored vaccine encoding the SARS-CoV-2 spike protein that is given as a two-dose series.
- • Four simultaneous randomized controlled trials of ChAdOx1 are being conducted in the U.K. (COV001 and COV002), Brazil (COV003) and South Africa (COV005).
- This updated analysis included outcome data from all 4 study sites and reported additional exploratory analyses demonstrating the efficacy of a single dose of vaccine and the impact of varying the interval between the prime and booster dose.
- An interim efficacy analysis that included outcome data from COV002 and COV003 was previously published and reported an overall vaccine efficacy of 70.4% (95.8% CI, 54.8-80.6).
- Across all 4 trials, 24,422 participants in the United Kingdom, Brazil and South Africa were recruited and vaccinated.
- COV001 is a single-blind Phase 1/2 randomized controlled trial conducted in the U.K. using meningococcal conjugate vaccine (MenACWY) as a comparator vaccine. The study was initially designed as a single-dose study (of 5x1010 vp, or “standard dose”), but later amended to include two doses.
- COV002 is a single-blind Phase 2/3 randomized controlled trial conducted in the U.K. It was also initially designed as a single-dose study but later amended. There were two dosage groups: low-dose (2.2x1010 vp) or standard-dose prime with standard-dose booster.
- COV003 is a single-blind Phase 3 randomized controlled trial conducted in Brazil. All participants received two doses of vaccine at a dose of 3.5-6.5x1010 vp given 4-12 weeks apart.
- COV005 is a double-blind Phase 1/2 RCT conducted in South Africa. All participants received two doses of vaccine at a dose of 3.5-6.5x1010 vp given 4 weeks apart.
- Of the 17,178 participants included in the updated primary efficacy analysis, 8,597 received the Oxford-AstraZeneca COVID-19 vaccine and 8,581 received the control vaccine.
- 52.0% (N=8,948) of these participants were from the U.K. trials; 39.3% (N=6,753) from the Brazil trial; and 8.6% (N=1,477) from the South Africa trial.
- 83.9% (N=14,413) of this study population was aged 18-55 years; 10.4% (N=1,792) aged 56-69 years; and 5.7% (N=973) aged ≥70 years.
- 56.4% (N=9,696) of the population was female.
- Patients included in the primary efficacy analysis:
- Were seronegative for SARS-CoV-2 N protein at baseline;
- Had no evidence of SARS-CoV-2 infection by PCR testing through day 14 after dose 1 of vaccine; and
- Had at least 14 days of follow-up after receiving the second dose.
- Patients included in the single-dose efficacy analysis were only included if they had no evidence of SARS-CoV-2 infection by PCR testing through day 21 after dose 1 of vaccine, and at least 22 days of follow-up after dose 1.
- The reduction in virologically confirmed symptomatic COVID-19, defined as a positive PCR test for SARS-CoV-2 with at least one of the following symptoms starting 14 days after dose 2 of the vaccine: fever ≥37.8°C, cough, shortness of breath, anosmia or ageusia .
- The reduction in virologically confirmed symptomatic COVID-19, defined as a positive PCR test for SARS-CoV-2 with at least one of the following symptoms starting 21 days after dose 1 of the vaccine: fever ≥37.8°C, cough, shortness of breath, anosmia or ageusia .
- Primary symptomatic COVID-19 occurred at least 14 days after dose 2 in 84 members of the Oxford-AstraZeneca vaccine arm and 248 members of the control group, yielding an overall vaccine efficacy of 66.7% (95% CI, 57.4-74.0%).
- In secondary analyses by dosage group:
- In the group that received two standard doses, there were 74 cases of symptomatic COVID-19 among those who received the Oxford-AstraZeneca vaccine and 197 in the control group, yielding an SD/SD vaccine efficacy of 63.1% (95% CI, 51.8-71.7).
- In the group that received a low dose prime followed by a standard dose booster (LD/SD), there were 10 cases of symptomatic COVID-19 among those who received the Oxford-AstraZeneca vaccine and 51 in the control group, for an LD/SD vaccine efficacy of 80.7% (95% CI, 62.1-90.2).
- There were zero COVID-19 related hospitalizations in the vaccinated group from day 22 after dose 1 of the vaccine, compared to 15 hospitalizations in the control group, for a vaccine efficacy against COVID-19-related hospitalization of 100% (95% CI, 72.2-100).
- In exploratory analyses modeling the impact of lengthening the prime-boost dosing interval:
- SD/SD vaccine efficacy against symptomatic COVID-19 starting 14 days after dose 2 was 55.1% when the interval was <6 weeks (95% CI, 33.0-69.9) and 81.3% when the interval was >12 weeks (95% CI, 60.3-91.2).
- Single-dose vaccine efficacy against symptomatic COVID-19 in the first 90 days after vaccination was 76.0% (95% CI, 59.3-85.9), but there was no evidence of against asymptomatic infection.
- This was an interim analysis of an ongoing clinical trial; longer and more complete follow-up is needed to confirm the results.
- The trials were not designed to determine if vaccine efficacy differed by dose interval.
Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomized controlled trials in Brazil, South Africa, and the UK (Voysey, December 2020).
Overall, in this pooled interim analysis of 4 clinical trials (ranging from phase 1/2 to 3), ChAdOx1 nCoV-19 was effective and preventing symptomatic COVID-19 disease and was safe at a median time of follow up of 2 months for people receiving 2 doses.
- This analysis includes data from blinded phase clinical trials of the vaccine: COV001 (UK), COV002 (UK), COV003 (Brazil), and COV005 (South Africa)
- CoV001 and COV005 were phase 1/2 trials, and COV002 and COV003 were phase 2/3 and 3, respectively.
- The phase 1 study (COV001) included an efficacy cohort and the phase 2 and 3 studies (COV002, COV003, and COV005) expanded enrollment to a wider population of participants with higher likelihood of exposure to the virus, such as health care workers.
- Participants were randomized to receive either AZD1222, the meningococcal conjugate vaccine MenACWY (COV001, COV002), MenACWY with the first placebo dose and saline for the second dose (COV003) or saline (COV005).
- Participants in the ChAdOx1 nCoV-19 group received two doses containing 5×1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial inadvertently received a half dose as their first dose due to a manufacturing error (low dose) and a standard dose as their second dose (LD/SD cohort).
- 23,848 participants were enrolled and 11,636 participants (7,548 in the UK; 4,088 in Brazil) were included in the interim primary efficacy analysis.
- >90% of participants were 18-55 years old and white.
- Patients were excluded if they had a baseline seropositive status, or if their baseline seropositive status was unknown.
- Patients were also excluded if they had NAAT-positive swabs within 14 days after the second vaccination.
- Virologically confirmed, symptomatic COVID-19, defined as a NAAT-positive sample and at least one of the following symptoms: fever > 37.8C, cough, shortness of breath, anosmia or ageusia more than 14 days after a second dose.
- Serious adverse events were a secondary endpoint, as were cases occurring more than 21 days after the first standard dose in participants who received only one standard dose.
- In pooled analyses of the trials (11,636 patients), there were 131 symptomatic cases of COVID-19 in LD/SD or SD/SD recipients (30 cases in the vaccine arm vs. 101 in the control group).
- Vaccine efficacy was 70.4%.
- In participants who received two standard-dose vaccines, vaccine efficacy was 62.1% (95% CI 41.0–75.7), whereas in those who received a low dose as their first dose of vaccine, efficacy was higher at 90.0% (67.4–97.0).
- From 21 days after the first dose, there were 10 cases hospitalized for COVID-19, all in the control arm.
- The analysis met its primary endpoint showing protection from COVID-19 occurring >14 days after receiving 2 doses of the vaccine.
- Safety data was available from 74,341 person-months of follow-up after first dose (median 3.4 months) and 29,060 person-months of follow-up after two doses (median 2 months).
- Serious adverse events occurred in 168 participants; 79 of these were in the vaccinated group, and 89 in the placebo group.
- Three adverse events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group (transverse myelitis occurring 14 days after the second vaccine dose), one in the control group (hemolytic anemia), and one in a participant who remains masked to group allocation (fever to >40C two days after receiving either the vaccine or placebo).
- Differences in dose amounts and the timing of dose administration between the four trials makes it difficult to consider the populations to be a single cohesive group for analysis.
- A majority of the participants were white, which may limit generalizability.
- The numbers of patients older than 55 was relatively small.
- Questions remain regarding the optimal dose and timing of dose, but additional trials are underway.
Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) COVID-19 Vaccine (Falsey, September 2021)
Overall, in this Phase 3 multinational (U.S., Chile, Peru) randomized, double-blind, placebo-controlled trial, AZD1222 (ChAdOx1 nCoV-19) given as a two-dose series was effective at preventing symptomatic COVID-19 and was safe at a median time to follow-up of two months.
- In a Phase 3 multinational randomized placebo-controlled efficacy clinical trial, 32,451 participants over 18 years of age from 88 sites in the U.S., Chile and Peru who were either healthy or had stable chronic medical conditions underwent 2:1 randomization.
- 21,635 participants were randomized to receive AZD1222 (at a dose of 5 x 1010 viral particles), and 10,816 were randomized to receive saline placebo. Vaccines were given on a two-dose schedule 28 days
- 6% of participants were men, and 79% were White.
- Virologically confirmed, symptomatic COVID-19, more than 14 days after the second dose, in individuals who were seronegative at baseline.
- Vaccine efficacy against symptomatic COVID-19 was 74.0% (95% CI, 65.3 to 80.5). Similar estimates were observed regardless of age, sex, racial or ethnic group, or underlying comorbidities.
- Most of the COVID-19 illnesses that contributed to the vaccine efficacy calculation occurred in the United States.
- The trial was briefly paused when a participant in a parallel study of AZD1222 in the U.K. developed transverse myelitis; when the trial was resumed, 775 participants received their second dose outside the 28-day window. Vaccine efficacy in this subgroup was similar to the overall study.
- Vaccine efficacy against severe outcomes was >90%.
- There were no cases in either group of thrombosis with thrombocytopenia, cerebral venous sinus thrombosis or venous thrombosis in unusual locations.
- There was no imbalance in neurologic adverse events of special interest.
- Limited follow-up, so durability of efficacy remains unknown — analysis is ongoing.
- Low racial and ethnic diversity of study population.
- The follow-up period did not include time when the Delta variant was predominant.
- The trial did not include children, immunocompromised or pregnant people.
Efficacy of the ChAdOx1 nCoV-19 COVID-19 Vaccine Against the B.1.351 Variant (Madhi, February 2021).
In this randomized controlled trial, 2,026 participants in South Africa aged 18-<65 years without HIV infection were randomized 1:1 to receive two doses 3-5 weeks apart of standard dose Oxford-AstraZeneca COVID-19 vaccine or placebo. Of these, 1,467 SARS-CoV-2 seronegative individuals were included in the primary efficacy analysis, with a median age of 31 years and 56.5% identifying as male. In live virus or pseudovirus neutralization assays using receptor-binding domain triple mutant viruses (containing only K417N, E484K and N501Y) or B.1.351 (SARS-CoV-2 variant first identified in South Africa) spike protein, sera from Oxford-AstraZeneca vaccine recipients displayed reduced or absent neutralization activity (as compared with D614G virus). There were 42 total cases of symptomatic COVID-19: 19 among ChAdOx1 recipients (15 mild, 4 moderate) and 23 among placebo recipients (17 mild, 6 moderate). There were no cases of severe disease or hospitalization, giving an overall vaccine efficacy of 21.9% (95% CI, -49.9-59.8). Forty-one (97.6%) of the 42 SARS-CoV-2 viruses involved in primary endpoint cases were sequenced, of which 39 (95.1%) were the B.1.351 variant. In a post-hoc analysis limited to cases occurring before Oct. 31, 2020 (when the B.1.351 variant emerged), vaccine efficacy was 75.4% (95% CI, 8.7-95.5).
Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomized, controlled, Phase 2/3 trial (Ramasamy, December 2020).
In this Phase 2/3 single-blind randomized controlled dosage-escalation trial (COV002), 560 participants aged 18 years and older were randomized to receive either one or two low doses or standard doses of Oxford-AstraZeneca vaccine, with MenACWY as a comparator. Booster doses were given 28 days after dose 1. Solicited adverse events in the COVID-19 vaccine arm were predominantly mild or moderate in severity and most frequently included injection site pain and tenderness, fatigue, headache and muscle ache. Reactogenicity was less after the booster dose compared with the prime dose, and adverse reactions were less common in older cohorts. Antibodies against SARS-CoV-2 spike were similar at day 28 after prime vaccination with both low-dose and standard-dose vaccine. At day 56, antibody and neutralization titers were higher among boost recipients (compared with single dose recipients) but did not vary by age or dosage regimen.
Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses (Barrett, December 2020).
In this follow-up immunogenicity study, vaccine-arm COV001 participants received a second low-dose or standard-dose vaccine at day 56. Data from the small number of participants who received a booster dose at day 28 were also included in the analysis. Anti-SARS-CoV-2 spike or receptor-binding domain antibodies increased after booster vaccination, similar to previous analysis. Furthermore, the ability of these antibodies to support antibody-dependent monocyte phagocytosis and antibody-dependent neutrophil phagocytosis was increased following booster vaccination, with a trend toward a greater increase when the prime-boost dosing interval was 56 rather than 28 days.
Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a Phase 1/2, single-blind, randomized controlled trial (Folegatti, August 2020).
In this Phase 1/2 single-blind randomized controlled trial (COV001), 1,077 adults aged 18-55 years were randomized 1:1 to receive a single standard dose of Oxford-AstraZeneca vaccine or MenACWY. Ten participants received a non-randomized non-blinded booster dose of Oxford-AstraZeneca vaccine at 28 days after dose 1. Solicited adverse events in recipients of ChAdOx1 were predominantly mild or moderate in severity and most frequently included injection site pain (67%) and tenderness (83%), fatigue (70%), headache (68%) and muscle ache (60%). Reactogenicity was less after the second dose in the cohort that received two doses of vaccine, though confidence intervals were wide. Antibodies against SARS-CoV-2 spike peaked by day 28 after vaccination. Most, but not all, Oxford-AstraZeneca recipients developing neutralizing titers after a single dose of vaccine, compared with all (100%) of the individuals in the prime-boost cohort.