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The drug, a combination of two antibodies called AZD7442, reduced the risk of severe Covid-19 or death by 50 per cent in non-hospitalised patients who have had symptoms for seven days or less, the Anglo-Swedish drugmaker said on Monday.
The risk reduction was even better in patients who started therapy within just five days of initial symptoms, but AstraZeneca joins an already crowded field of medicines that were shown to prevent deterioration in patients with mild disease when given soon after diagnosis.
AstraZeneca executive Mene Pangalos said in a media call that the treatment results would mainly underscore the potential future use as a non-vaccine prevention.
"If and when this is approved it will be used in the treatment setting as well. But the real differentiator for this antibody is going to be in the prophylactic setting," he said.
Similar therapies made with a class of drugs called monoclonal antibodies are being developed by Regeneron, Eli Lilly and GlaxoSmithKline with partner Vir...
Oxford–AstraZeneca COVID-19 vaccine
The Oxford–AstraZeneca COVID-19 vaccine, codenamed AZD1222, and sold under the brand names Covishield and Vaxzevria among others, is a viral vector vaccine for prevention of COVID-19. Developed in the United Kingdom by the Oxford University and British-Swedish company AstraZeneca, it is given by intramuscular injection, using as a vector the modified chimpanzee adenovirus ChAdOx1. Studies carried out in 2020 showed that the efficacy of the vaccine is 76.0% at preventing symptomatic COVID-19 beginning at 22 days following the first dose and 81.3% after the second dose. A study in Scotland found that, for symptomatic COVID-19 infection after the second dose, the vaccine is 81% effective against the Alpha variant , and 61% against the Delta variant .
The vaccine is stable at refrigerator temperatures and has a good safety profile, with side effects including injection-site pain, headache, and nausea, all generally resolving within a few days. More rarely, anaphylaxis may occur has 268 reports out of some 21.2 million vaccinations as of 14 April 2021). In very rare cases the vaccine has been associated with an increased risk of blood clots when in combination with low levels of blood platelets. According to the European Medicines Agency as of 4 April 2021, a total number of 222 cases of extremely rare blood clots among 447 million people reported from the European Economic Area, this percentage includes the UK, .
On 30 December 2020, the vaccine was first approved for use in the UK vaccination programme, and the first vaccination outside of a trial was administered on 4 January 2021. The vaccine has since been approved by several medicine agencies worldwide, such as the European Medicines Agency , and the Australian Therapeutic Goods Administration , and was approved for an Emergency Use Listing by the World Health Organization . By July 2021, one billion doses of the vaccine had been released to more than 170 countries worldwide. Some countries have limited its use to elderly people at higher risk for severe COVID-19 illness due to concerns over the very rare side effects of the vaccine in younger individuals.
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Medical uses
The Oxford–AstraZeneca COVID-19 vaccine is used to provide protection against infection by the SARS-CoV-2 virus in order to prevent COVID-19 in adults aged 18 years and older. The medicine is administered by two 0.5 ml doses given by intramuscular injection into the deltoid muscle . The initial course consists of two doses with an interval of 4 to 12 weeks between doses. The World Health Organization recommends an interval of 8 to 12 weeks between doses for optimal efficacy.
There is no evidence that a third booster dose dose is needed to prevent severe disease in healthy adults.
Effectiveness
Preliminary data from a real-world study in Botucatu in Brazil, where the Gamma variant predominates, found a 71% reduction in symptomatic cases after 81% of the population received the first dose.
Preliminary data from a study in Brazil with 61 million individuals from 18 January to 30 June 2021 indicate that the effectiveness against infection, hospitalization and death is similar between most age groups, but protection against all these outcomes is significantly reduced in those aged 90 or older, attributable to immunosenescence.
A vaccine is generally considered effective if the estimate is =50% with a >30% lower limit of the 95% confidence interval. Effectiveness is generally expected to slowly decrease over time.
Contraindications
The Oxford–AstraZeneca COVID-19 vaccine should not be administered to people who have had capillary leak syndrome.
Adverse effects
The most common side effects in the clinical trials were usually mild or moderate and got better within a few days after vaccination.
Vomiting, diarrhoea, fever, swelling, redness at the injection site and low levels of blood platelets occurred in less than 1 in 10 people. Enlarged lymph nodes, decreased appetite, dizziness, sleepiness, sweating, abdominal pain, itching and rash occurred in less than 1 in 100 people.
An increased risk of the rare and potentially fatal thrombosis with thrombocytopenia syndrome has been associated with mainly younger female recipients of the vaccine. Analysis of VigiBase reported embolic and thrombotic events after vaccination with Oxford–AstraZeneca, Moderna and Pfizer vaccines, found a temporally related incidence of 0.21 cases per 1 million vaccinated-days.
Anaphylaxis and other allergic reactions are a known side effect of ADZ1222 that should be given under close supervision. The European Medicines Agency has assessed 41 cases of anaphylaxis from around 5 million vaccinations in the United Kingdom.
Capillary leak syndrome is a possible side effect of the vaccine.
The European Medicines Agency listed Guillain-Barré syndrome as a very rare side effect of Vaxzevria and added a warning in the product information.
Pharmacology
The Oxford–AstraZeneca COVID-19 vaccine is a replication-deficient simian adenovirus vector, containing the full-length codon-optimised coding sequence of SARS-CoV-2 spike protein along with a tissue plasminogen activator leader sequence.
The adenovirus is called replication-deficient because some of its essential genes were deleted and replaced by a gene coding for the spike protein. Following vaccination, the adenovirus vector enters the cells and releases its genes, in the form of DNA, which are transported to the cell nucleus; thereafter the cell's machinery does the transcription from DNA into mRNA and the translation into proteins.
The protein of interest is the spike protein, an external protein that enables the SARS-type coronavirus to enter cells through the enzymatic domain of ACE2. Producing it following vaccination will prompt the immune system to attack the coronavirus through antibodies and T-cells if it later infects the body.
Manufacturing
To manufacture the vaccine the virus is propagated on HEK 293 cell lines and then purified multiple times to completely remove the cell culture.
The vaccine costs around US$3 to US$4 per dose to manufacture. On 17 December 2020, a tweet by the Belgian Budget State Secretary revealed that the European Union would pay €1.78 per dose, The New York Times suggesting the lower price might relate to factors including investment in vaccine production infrastructure by the EU.
As of March 2021 the vaccine active substance is being produced at several sites worldwide, with AstraZeneca claiming to have established 25 sites in 15 countries. The UK sites are Oxford and Keele with bottling and finishing in Wrexham. Other sites include the Serum Institute of India at Pune. The Halix site at Leiden was approved by the EMA on 26 March 2021, joining three other sites approved by the EU.
History
The vaccine arose from a collaboration between Oxford University's Jenner Institute and Vaccitech, a private company spun off from the university, with financing from Oxford Sciences Innovation, Google Ventures, and Sequoia Capital, among others. The first batch of the COVID-19 vaccine produced for clinical testing was developed by Oxford University's Jenner Institute and the Oxford Vaccine Group in collaboration with Italian manufacturer Advent Srl located in Pomezia. The team is led by Sarah Gilbert, Adrian Hill, Andrew Pollard, Teresa Lambe, Sandy Douglas and Catherine Green.
Early development
In February 2020, the Jenner Institute agreed a collaboration with the Italian company Advent Srl for the production of a batch of 1,000 doses of a vaccine candidate for clinical trials. Originally, Oxford intended to donate the rights to manufacture and market the vaccine to any drugmaker who wanted to do so, but after the Gates Foundation urged Oxford to find a large company partner to get its COVID-19 vaccine to market, the university backed off of this offer in May 2020. The UK government then encouraged Oxford to work with AstraZeneca, a company based in Europe, instead of Merck & Co., a US-based company . Government ministers also had concerns that a vaccine manufactured in the US would not be available in the UK, according to anonymous sources in The Wall Street Journal. Financial considerations at Oxford and spin-out companies may have also played a part in the decision to partner with AstraZeneca.
An initially not-for-profit licencing agreement was signed between the university and AstraZeneca PLC, in May 2020, with 1 billion doses of potential supply secured, with the UK reserving access to the initial 100 million doses. Furthermore, the US reserved 300 million doses, as well as the authority to perform Phase III trials in the US. The collaboration was also granted GB£68m of UK government funding, and US$1.2bn of US government funding, to support the development of the vaccine. In June 2020, the US National Institute of Allergy and Infectious Diseases confirmed that the third phase of trials for the vaccine would begin in July 2020. On 4 June, AstraZeneca announced that the COVAX program for equitable vaccine access managed by the WHO and financed by CEPI and Gavi had spent $750m to secure 300 million doses of the vaccine to be distributed to low-income or under-developed countries.
Preliminary data from a study that reconstructed funding for the vaccine indicates that funding was at least 97% public, almost all from UK government departments, British and American scientific institutes, the European Commission and charities.
Clinical trials
In July 2020, AstraZeneca partnered with IQVIA to accelerate the timeframe for clinical trials being planned or conducted in the US. On 31 August, AstraZeneca announced that it had begun enrolment of adults for a US-funded, 30,000-subject late-stage study.
Clinical trials for the vaccine candidate were halted worldwide on 8 September, as AstraZeneca investigated a possible adverse reaction which occurred in a trial participant in the UK. Trials were resumed on 13 September after AstraZeneca and Oxford, along with UK regulators, concluded it was safe to do so. AstraZeneca was later criticised for refusing to provide details about potentially serious neurological side effects in two trial participants who had received the experimental vaccine in the UK. While the trials resumed in the UK, Brazil, South Africa, Japan and India, the US did not resume clinical trials of the vaccine until 23 October. This was due to a separate investigation by the Food and Drug Administration surrounding a patient illness that triggered a clinical hold, according to the US Department of Health and Human Services Secretary Alex Azar.
The results of the COV002 phase II/III trial showed that immunity lasts for at least one year after a single dose.
Results of Phase III trial
On 23 November 2020, the first interim data was released by Oxford University and AstraZeneca from the vaccine's ongoing Phase III trials. The interim data reported a 70% efficacy, based on combined results of 62% and 90% from different groups of participants who were given different dosages. The decision to combine results from two different dosages was met with criticism from some who questioned why the results were being combined. AstraZeneca responded to the criticism by agreeing to carry out a new multi-country trial using the lower dose, which had led to the 90% claim.
The full publication of the interim results from four ongoing Phase III trials on 8 December allowed regulators and scientists to begin evaluating the vaccine's efficacy. The December report showed that at 21 days after the second dose and beyond, there were no hospitalisations or severe disease in those who received the vaccine, compared to 10 cases in the control groups. The rate of serious adverse events was balanced between the active and control groups, which suggested that the active vaccine did not pose safety concerns beyond a rate experienced in the general population. One case of transverse myelitis was reported 14 days after the second-dose was administered as being possibly related to vaccination, with an independent neurological committee considering the most likely diagnosis to be of an idiopathic, short-segment, spinal cord demyelination. The other two cases of transverse myelitis, one in the vaccine group and the other in the control group, were considered to be unrelated to vaccination.
A subsequent analysis, published on 19 February 2021, showed an efficacy of 76.0% at preventing symptomatic COVID-19 beginning at 22 days following the first dose, increasing to 81.3% when the second dose is given 12 weeks or more after the first. However, the results did not show any protection against asymptomatic COVID-19 following only one dose. Beginning 14 days following timely administration of a second dose, with different duration from the first dose depending on trials, the results showed 66.7% efficacy at preventing symptomatic infection, and the UK arm was inconclusive as to the prevention of asymptomatic infection. Efficacy was higher at greater intervals between doses, peaking at around 80% when the second dose was given at 12 weeks or longer after the first. Preliminary results from another study with 120 participants under 55 years of age showed that delaying the second dose by up to 45 weeks increases the resulting immune response and that a booster dose given at least six months later produces a strong immune response. A booster dose may not be necessary, but it alleviates concerns that the body would develop immunity to the vaccine's viral vector, which would reduce the potency of annual inoculations.
On 22 March 2021, AstraZeneca released interim results from the phase III trial conducted in the US that showed efficacy of 79% at preventing symptomatic COVID-19 and 100% efficacy at preventing severe disease and hospitalisation. The next day, the National Institute of Allergy and Infectious Diseases published a statement countering that those results may have relied on 'outdated information' that may have provided an incomplete view of the efficacy data. AstraZeneca later revised its efficacy claim to be 76% after further review of the data. On 29 September 2021, Astrazeneca shows of 74% efficacy rate in the US trial.
Single dose effectivess
A study on the effectiveness of a first dose of the Pfizer–BioNTech or Oxford–AstraZeneca COVID-19 vaccines against COVID-19 related hospitalisation in Scotland was based on a national prospective cohort study of 5.4 million people. Between 8 December 2020 and 15 February 2021, 1,137,775 participants were vaccinated in the study, 490,000 of whom were given the Oxford–AstraZeneca vaccine. The first dose of the Oxford–AstraZeneca vaccine was associated with a vaccine effect of 94% for COVID-19-related hospitalisation at 28–34 days post-vaccination. Combined results showed a significant vaccine effect for prevention of COVID-19-related hospitalisation, which was comparable when restricting the analysis to those aged =80 years . The majority of the participants over the age of 65 were given the Oxford–AstraZeneca vaccine.
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Nasal spray
On 25 March 2021, the University of Oxford announced the start of a phase I clinical trial to investigate the efficacy of an intranasal spray method.
Approvals
The first country to issue a temporary or emergency approval for the Oxford–AstraZeneca vaccine was the UK. The Medicines and Healthcare products Regulatory Agency began a review of efficacy and safety data on 27 November 2020, followed by approval for use on 30 December 2020, becoming the second vaccine approved for use in the national vaccination programme. The BBC reported that the first person to receive the vaccine outside of clinical trials was vaccinated on 4 January 2021.
The European Medicines Agency began review of the vaccine on 12 January 2021, and stated in a press release that a recommendation could be issued by the agency by 29 January, followed by the European Commission deciding on a conditional marketing authorisation within days. On 29 January 2021, the EMA recommended granting a conditional marketing authorisation for AZD1222 for people 18 years of age and older, and the recommendation was accepted by the European Commission the same day. Prior to approval across the EU, the Hungarian regulator unilaterally approved the vaccine instead of waiting for EMA approval.
On 30 January 2021, the Vietnamese Ministry of Health approved the AstraZeneca vaccine for use, becoming the first vaccine to be approved in Vietnam. The vaccine has since been approved by a number of non-EU countries, including Argentina, Bangladesh, Brazil, the Dominican Republic, El Salvador, India, Malaysia, Mexico, Nepal, Pakistan, the Philippines, Sri Lanka, and Taiwan regulatory authorities for emergency usage in their respective countries.
South Korea granted approval of the AstraZeneca vaccine on 10 February 2021, thus becoming the first vaccine to be approved for use in that country. The regulator recommended the two-shot regimen be used in all adults, including the elderly, noting that consideration is needed when administering the vaccine to individuals over 65 years of age due to limited data from that demographic in clinical trials. On the same day, the World Health Organization issued interim guidance and recommended the AstraZeneca vaccine for all adults, its Strategic Advisory Group of Experts also having considered use where variants were present and concluded there was no need not to recommend it.
Later in February, the government and regulatory authorities in Australia and Canada granted approval for temporary use of the vaccine.
Safety review
On 11 March 2021, the European Medicines Agency stated that there is no indication that vaccination has been the cause of the observed clotting issues, which were not listed as side effects of the vaccine. At the time, according to the EMA, the number of thromboembolic events in vaccinated people was no higher than that seen in the general population. As of 11 March 2021, 30 cases of thromboembolic events had been reported among the almost 5 million people vaccinated in the European Economic Area. The UK's MHRA also stated that after more than 11 million doses administered, it had not been confirmed that the reported blood clots were caused by the vaccine and that vaccinations would not be stopped. On 12 March 2021 the WHO stated that a causal relationship had not been shown and that vaccinations should continue. AstraZeneca confirmed on 14 March 2021 that after examining over 17 million people who have been vaccinated with the vaccine, no evidence of an increased risk of blood clots in any particular country was found. The company reported that as of 8 March 2021, across the EU and UK, there had been 15 events of deep vein thrombosis and 22 events of pulmonary embolism reported among those given the vaccine, which is much lower than would be expected to occur naturally in a general population of that size.
On 15 March 2021, the German Paul-Ehrlich Institute reported that out of 1.6 million vaccinations, seven cases of cerebral vein thrombosis in conjunction with a deficiency of blood platelets had occurred. According to the PEI, the number of cases of cerebral vein thrombosis after vaccination was statistically significantly higher than the number that would occur in the general population during a similar time period. These reports prompted the PEI to recommended a temporary suspension of vaccinations until the EMA had completed their review of the cases.
The World Health Organization issued a statement on 17 March, regarding the AstraZeneca COVID-19 vaccine safety signals, and still considers the benefits of the vaccine to outweigh its potential risks, further recommending that vaccinations continue. On 18 March, the EMA announced that out of the around 20 million people who had received the vaccine, general blood clotting rates were normal, but that it had identified seven cases of disseminated intravascular coagulation, and eighteen cases of cerebral venous sinus thrombosis. A causal link with the vaccine was not proven, but the EMA said it would conduct further analysis and recommended informing people eligible for the vaccine of the fact that the possibility it may cause rare clotting problems had not been disproven. The EMA confirmed that the vaccine's benefits outweighed the risks. On 25 March, the EMA released updated product information.
According to the EMA, 100,000 cases of blood clots occur naturally each month in the EU, and the risk of blood clots was not statistically higher in the vaccinated population. The EMA noted that COVID-19 itself causes an increased risk of the development of blood clots, and as such the vaccine would lower the risk of the formation of blood clots even if the 15 cases' causal link were to be confirmed. Italy resumed vaccinations after the EMA's statement, with most of the remaining European countries following suit and resuming their AstraZeneca inoculations shortly thereafter. To reassure the public of the vaccine's safety, the British and French Prime Ministers, Boris Johnson and Jean Castex, had themselves vaccinated with it in front of the media shortly after the restart of the AstraZeneca vaccination campaigns in the EU.
On 13 April 2021, the EMA issued its direct healthcare professional communication about the vaccine. The DHPC indicated that a causal relationship between the vaccine and blood clots in combination with low blood platelets was plausible and identified it as a very rare side effect of the vaccine. According to the EMA these very rare adverse events occur in around 1 out of 100,000 vaccinated people.
Efficacy against variants
A study published in April 2021 by researchers from the COVID-19 Genomics United Kingdom Consortium, the AMPHEUS Project, and the Oxford COVID-19 Vaccine Trial Group indicated the Oxford–AstraZeneca vaccine showed somewhat reduced efficacy against infection with the Alpha variant , with 70.4% efficacy in absolute terms against Alpha versus 81.5% against other variants. Despite this, the researchers concluded that the vaccine remained effective at preventing symptomatic infection from this variant and that vaccinated individuals infected symptomatically typically had shorter duration of symptoms and less viral load, thereby reducing the risk of transmission. Following the identification of notable variants of concern, concern arose that the E484K mutation, present in the Beta and Gamma variants , could evade the protection given by the vaccine. In February 2021, the collaboration was working to adapt the vaccine to target these variants, with the expectation that a modified vaccine would be available 'in a few months' as a 'booster' given to people who had already completed the two-dose series of the original vaccine.
In June 2021, AstraZeneca published a press release confirming undergoing Phase II/III trials of an AZD2816 COVID-19 variant vaccine candidate. The new vaccine would be based on the current Vaxzevria adenoviral vector platform but modified with spike proteins based on the Beta variant. Phase II/III trials saw 2849 volunteers participating from UK, South Africa, Brazil and Poland with parallel dosing of both the current Oxford-AstraZeneca vaccine and the variant vaccine candidate. By September 2021, AZD2816 vaccine candidate is still undergoing Phase II/III trials with intent to switch to this vaccine vaccine if approved by goverment regulators. Particularly the government of Thailand, with delivery of additional 60 million doses of AstraZeneca COVID-19 Vaccine agreed for 2022.
Heterologous prime-boost vaccination
See also: COVID-19 vaccine clinical research § Heterologous prime-boost vaccination In December 2020, a clinical trial was registered to examine a heterologous prime-boost vaccination course consisting of one dose of the Oxford–AstraZeneca vaccine followed by Sputnik Light based on the Ad26 vector 29 days later.
After suspensions due to rare cases of blood clots in March 2021, Canada and several European countries recommended receiving a different vaccine for the second dose. Despite the lack of clinical data on the efficacy and safety of such heterologous combinations, some experts believe that doing so may boost immunity, and several studies have begun to examine this effect.
In June 2021, preliminary results from a study of 463 participants showed that a heterologous prime-boost vaccination course consisting of one dose of the Oxford–AstraZeneca vaccine followed by one dose of the Pfizer–BioNTech vaccine produced the strongest T cell activity and an antibody level almost as high as two doses of the Pfizer-BioNTech vaccine. The reversal of the order resulted in T cell activity at half the potency and one-seventh the antibody levels, the latter still five times higher than two doses of Oxford–AstraZeneca. The lowest T cell activity was observed in homologous courses, when both doses were of the same vaccine.
In July 2021, a study of 216 participants found that a heterologous prime-boost vaccination course consisting of one dose of the Oxford–AstraZeneca vaccine followed by one dose of the Moderna vaccine produced a similar level of neutralizing antibodies and T cell responses with increased spike-specific cytotoxic T cells compared to a homologous course consisting of two doses of the Moderna vaccine.