I got my second Pfizer COVID-19 shot today! Three weeks ago, a friend called to say that her son-in-law had talked to a doctor at Parkland Hospital — which serves as Dallas County’s public hospital — who said that you didn’t need an appointment to get a shot there. My friend went that day, and I followed her about 30 minutes later. She had to wait in a longer line than I did. Timing is everything. The following week I told a guy friend at Sunday school about it. He was hesitant because there was nothing on Parkland’s website about walk-in shots. I called the hospital and got an employee there to admit that you are supposed to have an appointment, but if you show up, you can get the shot. So, he went and got the shot too. However, later I took an elderly friend there to get the shot, and she was told it was by appointment only. So, I guess there was a short window of time when appointments were not required, and the three of us made it in. It is almost like winning the Senior Sweepstakes. The main topic of conversation among over 65-year-olds is who has been vaccinated most recently, how did they get on the list so quickly and where did they go to get it. I have heard stories about people traveling two to three hours away just to get the COVID-19 shot. Let’s find out more about this lifesaving vaccine and how it will help all of us get back to living a normal life.
According to Wikipedia, a COVID‑19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 or SARS‑CoV‑2, the virus causing coronavirus disease 2019 or COVID‑19. Before the COVID-19 pandemic, there was an established body of knowledge about the structure and function of coronaviruses causing diseases like severe acute respiratory syndrome or SARS and Middle East respiratory syndrome or MERS, which enabled accelerated development of various vaccine technologies during early 2020. On January 10, 2020, the SARS-CoV-2 genetic sequence data was shared through GISAID — a global science initiative — and by March 19, the global pharmaceutical industry announced a major commitment to address COVID-19.
As of February 2021, 66 vaccine candidates are in clinical research, including 17 in Phase I trials, 23 in Phase I-II trials, 6 in Phase II trials and 20 in Phase III trials. Trials for four other candidates were terminated. In Phase III trials, several COVID‑19 vaccines demonstrate efficacy as high as 95% in preventing symptomatic COVID‑19 infections. As of February 2021, 11 vaccines are authorized by at least one national regulatory authority for public use: two RNA vaccines (Pfizer-BioNTech and Moderna), four conventional inactivated vaccines (BBIBP-CorV, Cobaxin, CoronaVac and CoviVac), four viral vector vaccines (Sputnik V, Oxford-AstraZeneca, Convidicea and Johnson & Johnson) and one peptide vaccine (EpiVacCorona).
Many countries have implemented phased distribution plans that prioritize those at highest risk of complications — such as the elderly — and those at high risk of exposure and transmission, such as healthcare workers. As of March 4, 2021, 283.58 million doses of COVID‑19 vaccine have been administered worldwide based on official reports from national health agencies. AstraZeneca-Oxford anticipates producing 3 billion doses in 2021, Pfizer-BioNTech 1.3 billion doses and Sputnik V, Sinopharm, Sinovac and Johnson & Johnson 1 billion doses each. Moderna targets producing 600 million doses and Convidicea 500 million doses in 2021. By December 2020, more than 10 billion vaccine doses had been preordered by countries, with about half of the doses purchased by high-income countries comprising 14% of the world's population.
Background
Prior to COVID‑19, a vaccine for an infectious disease had never been produced in less than several years — and no vaccine existed for preventing a coronavirus infection in humans. However, vaccines have been produced against several animal diseases caused by coronaviruses, including infectious bronchitis virus in birds, canine coronavirus and feline coronavirus, as of 2003. Previous projects to develop vaccines for viruses in the family Coronaviridae that affect humans have been aimed at severe acute respiratory syndrome or SARS and Middle East respiratory syndrome or MERS. Vaccines against SARS and MERS have been tested in nonhuman animals.
According to studies published in 2005 and 2006, the identification and development of novel vaccines and medicines to treat SARS was a priority for governments and public health agencies around the world at that time. As of 2020, there is no cure or protective vaccine proven to be safe and effective against SARS in humans. There is also no proven vaccine against MERS. When MERS became prevalent, it was believed that existing SARS research might provide a useful template for developing vaccines and therapeutics against a MERS-CoV infection. As of March 2020, there was one DNA-based MERS vaccine which completed Phase I clinical trials in humans and three others in progress, all being viral-vectored vaccines: two adenoviral-vectored (ChAdOx1-MERS, BVRS-GamVac) and one Modified Vaccinia Ankara or MVA-vectored (MVA-MERS-S).
The urgency to create a vaccine for COVID‑19 led to compressed schedules that shortened the standard vaccine development timeline, in some cases combining clinical trial steps over months, a process typically conducted sequentially over years. Multiple steps along the entire development path are evaluated, including the level of acceptable toxicity of the vaccine or its safety, targeting vulnerable populations, the need for vaccine efficacy breakthroughs, the duration of vaccination protection, special delivery systems such as oral or nasal rather than by injection, dose regimen, stability and storage characteristics, emergency use authorization before formal licensing, optimal manufacturing for scaling to billions of doses and dissemination of the licensed vaccine. Timelines for conducting clinical research – normally a sequential process requiring years – are being compressed into safety, efficacy and dosing trials running simultaneously over months, potentially compromising safety assurance. As an example, Chinese vaccine developers and the government Chinese Center for Disease Control and Prevention began their efforts in January 2020, and by March were pursuing numerous candidates on short timelines, with the goal of showcasing Chinese technology strengths over those of the United States and to reassure the Chinese people about the quality of vaccines produced in China.
Planning and development
Since early 2020, vaccine development has been expedited via unprecedented collaboration in the multinational pharmaceutical industry and between governments. According to the Coalition for Epidemic Preparedness Innovations or CEPI, the geographic distribution of COVID‑19 vaccine development puts North American entities having about 40% of the activity compared to 30% in Asia and Australia, 26% in Europe and a few projects in South America and Africa.
There have been several unique challenges with COVID-19 vaccine development. The rapid development and urgency of producing a vaccine for the COVID‑19 pandemic may increase the risks and failure rate of delivering a safe, effective vaccine. Additionally, research at universities is obstructed by physical distancing and closing of laboratories.
Vaccines must progress through several phases of clinical trials to test for safety, immunogenicity, effectiveness, dose levels and adverse effects of the candidate vaccine. Vaccine developers have to invest resources internationally to find enough participants for Phase II–III clinical trials when the virus has proved to be a "moving target" of changing transmission rate across and within countries, forcing companies to compete for trial participants; clinical trial organizers may encounter people unwilling to be vaccinated due to vaccine hesitancy or disbelieving the science of the vaccine technology and its ability to prevent infection. Even as new vaccines are developed during the COVID‑19 pandemic, licensure of COVID‑19 vaccine candidates requires submission of a full dossier of information on development and manufacturing quality.
Organizations
Internationally, the Access to COVID-19 Tools Accelerator is a G20 or Group of Twenty — an international forum for the governments and central bank governors from 19 countries and the European Union — and World Health Organization or WHO initiative announced in April 2020. It is a cross-discipline support structure to enable partners to share resources and knowledge. It comprises four pillars, each managed by two to three collaborating partners: Vaccines — also called "COVAX," Diagnostics, Therapeutics and Health Systems Connector. The WHO's April 2020 "R&D Blueprint (for the) novel Coronavirus" documented a "large, international, multisite, individually randomized controlled clinical trial" to allow "the concurrent evaluation of the benefits and risks of each promising candidate vaccine within 3–6 months of it being made available for the trial." The WHO vaccine coalition will prioritize which vaccines should go into Phase II and III clinical trials and determine harmonized Phase III protocols for all vaccines achieving the pivotal trial stage. Although the Trump administration of the United States had withdrawn its financial support of the WHO and ACT Accelerator in 2020, the United States reasserted its support of the WHO and COVAX on January 21, 2021 following the inauguration of President Joe Biden.
National governments have also been involved in vaccine development. Canada announced funding for 96 research vaccine research projects at Canadian companies and universities, with plans to establish a "vaccine bank" that could be used if another coronavirus outbreak occurs, and to support clinical trials and develop manufacturing and supply chains for vaccines. China provided low-rate loans to a vaccine developer through its central bank and "quickly made land available for the company" to build production plants. Three Chinese vaccine companies and research institutes are supported by the government for financing research, conducting clinical trial, and manufacturing. Great Britain formed a COVID‑19 vaccine task force in April 2020 to stimulate local efforts for accelerated development of a vaccine through collaborations of industry, universities and government agencies. It encompassed every phase of development from research to manufacturing. In the United States, the Biomedical Advanced Research and Development Authority or BARDA, a federal agency funding disease-fighting technology, announced investments to support American COVID‑19 vaccine development and manufacture of the most promising candidates. In May 2020, the government announced funding for a fast-track program called Operation Warp Speed.
Large pharmaceutical companies with experience in making vaccines at scale, including Johnson & Johnson, AstraZeneca and GlaxoSmithKline formed alliances with biotechnology companies, governments and universities to accelerate progression to an effective vaccine.
History
After a coronavirus was isolated in December 2019, its genetic sequence was published on January 11, 2020, triggering an urgent international response to prepare for an outbreak and hasten development of a preventive COVID-19 vaccine. Since early 2020, vaccine development has been expedited via unprecedented collaboration in the multinational pharmaceutical industry and between governments. By June 2020, tens of billions of dollars were invested by corporations, governments, international health organizations and university research groups to develop dozens of vaccine candidates and prepare for global vaccination programs to immunize against COVID‑19 infection. According to the Coalition for Epidemic Preparedness Innovations, the geographic distribution of COVID‑19 vaccine development puts North American entities having about 40% of the activity compared to 30% in Asia and Australia, 26% in Europe and a few projects in South America and Africa.
In February 2020, the WHO said it did not expect a vaccine against severe acute respiratory syndrome coronavirus 2 or SARS‑CoV‑2, the causative virus, to become available in less than 18 months. The rapidly growing infection rate of COVID‑19 worldwide during early 2020 stimulated international alliances and government efforts to urgently organize resources to make multiple vaccines on shortened timelines, with four vaccine candidates entering human evaluation in March.
On 24 June 2020, China approved the CanSino vaccine for limited use in the military and two inactivated virus vaccines for emergency use in high-risk occupations. On August 11, 2020, Russia announced the approval of its Sputnik V vaccine for emergency use, though one month later only small amounts of the vaccine had been distributed for use outside of the phase 3 trial.
The Pfizer-BioNTech partnership submitted an emergency use authorization request to the U.S. Food and Drug Administration for the mRNA vaccine BNT162b2 — active ingredient tozinameran — on November 20, 2020. On December 2, 2020, the United Kingdom's Medicines and Healthcare products Regulatory Agency or MHRA gave temporary regulatory approval for the Pfizer-BioNTech vaccine, becoming the first country to approve this vaccine and the first country in the Western world to approve the use of any COVID‑19 vaccine. As of December 21, 2020, many countries and the European Union have authorized or approved the Pfizer-BioNTech COVID‑19 vaccine. Bahrain and the United Arab Emirates granted emergency marketing authorization for BBIBP-CorV, manufactured by Sinopharm. On December 11, 2020, the FDA granted an emergency use authorization for the Pfizer-BioNTech COVID‑19 vaccine. A week later, it granted an EUA for mRNA-1273, the Moderna vaccine.
Trial and authorization status
Phase I trials test primarily for safety and preliminary dosing in a few dozen healthy subjects, while Phase II trials — following success in Phase I — evaluate immunogenicity, dose levels (efficacy based on biomarkers) and adverse effects of the candidate vaccine, typically in hundreds of people. A Phase I–II trial consists of preliminary safety and immunogenicity testing and is typically randomized and placebo-controlled, while determining more precise, effective doses. Phase III trials typically involve more participants at multiple sites, include a control group and test effectiveness of the vaccine to prevent the disease — an "interventional" or "pivotal" trial, while monitoring for adverse effects at the optimal dose. Definition of vaccine safety, efficacy and clinical endpoints in a Phase III trial may vary between the trials of different companies, such as defining the degree of side effects, infection or amount of transmission, and whether the vaccine prevents moderate or severe COVID‑19 infection.
A clinical trial design in progress may be modified as an “adaptive design” if accumulating data in the trial provide early insights about positive or negative efficacy of the treatment. Adaptive designs within ongoing Phase II–III clinical trials on candidate vaccines may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, avoiding duplication of research efforts and enhancing coordination of design changes for the solidarity trial across its international locations.
Efficacy
The effectiveness of a new vaccine is defined by its efficacy during clinical trials. The efficacy is the risk of getting the disease by vaccinated participants in the trial compared with the risk of getting the disease by unvaccinated participants. An efficacy of 0% means that the vaccine does not work, identical to placebo. An efficacy of 50% means that there are half as many cases of infection as in unvaccinated individuals.
It is not straightforward to compare the efficacies of the different vaccines because the trials were run with different populations, geographies and variants of the virus. In the case of COVID‑19, a vaccine efficacy of 67% may be enough to slow the pandemic, but this assumes that the vaccine confers sterilizing immunity, which is necessary to prevent transmission. Vaccine efficacy reflects disease prevention, a poor indicator of transmissibility of SARS‑CoV‑2 since asymptomatic people can be highly infectious. The FDA and the European Medicines Agency or EMA set a cutoff of 50% as the efficacy required to approve a COVID‑19 vaccine.
In efficacy calculations, symptomatic COVID-19 is generally defined as having both a positive PCR test and at least one or two of a defined list of COID-19 symptoms, although exact specifications vary between trials. The trial location also affects the reported efficacy because different countries have different prevalences of SARS-CoV-2 variants. Ranges below are 95%.
At the University of Oxford, researchers have as of early February 2021 begun enrolling volunteers in an 820-person trial to evaluate the efficacy of combining two different vaccines, a mix and match approach, as opposed to using two doses of the same vaccine. The ultimate goal of the study will be find whether the mix-and-match method is just as or more effective than the currently used practice. The study will use the shot developed by Pfizer and BioNTech with the University of Oxford and AstraZeneca shot, two vaccines which rely on different methods to deliver information to the cells of the recipient. BioNTech founder Uğur Şahin has voiced his opposition to the trial in December, stating that a study "will use up doses that people who need them could profit from, I am not happy about this," though Pfizer and AstraZeneca have supported the trials.
Variants
A preliminary study by Pfizer Inc. has indicated that there is, at most, only minor reduction of the company’s mRNA vaccine effectiveness against different SARS-CoV-2 variants. According to the U.S. Center for Disease Control and Prevention, most experts believe that due to the nature of the virus, the emergence of variants that completely escape the immune response — both natural and vaccine-induced — is considered unlikely.
T-cell immunity is under investigation as a potential solution to the problem of reduced effectiveness of vaccines against the relevant variants. This is because T-cells target multiple pieces of the virus. As the majority of genetic variation is on the spike protein, T-cells that attack other parts of the virus should be able to recognize new variants. Viral vector- and mRNA-based vaccines are believed to elicit the strongest T-cell response. This is believed to be the reason why the vaccine developed for yellow fever — an RNA virus like SARS-CoV-2 — has remained effective for so long; by targeting antigens within the virus that are unlikely to change, as opposed to those on the surface, it is unaffected by the majority of mutations. Companies including Emergex, Osivax and eTheRNA are targeting these internal antigens in the hope of creating a "universal" SARS-CoV-2 vaccine. Biotechnology firm Gritstone is also experimenting to develop a vaccine aimed specifically at creating T-cell immunity.
On January 29, 2021, a deputy of the Moscow City Duma, Darya Besedina, turned to the Russian Minister of Health with a request to fund the study of new strains and conduct research on the effectiveness of Russian vaccines against these strains. On February 10, 2021, the European Medicines Agency made a similar appeal to vaccine manufacturers. On February 15, 2021, Russian President Vladimir Putin instructed the government to deploy the sequencing of the genomes of Russian SARS-CoV-2 strains within a month, allocate funds for these studies and also check whether Russian vaccines are effective against new strains.
B.1.1.7 (United Kingdom) variant
In December 2020, a new SARS-CoV-2 variant, B.1.1.7, was identified in the UK. Early results suggest that both the Pfizer and Moderna vaccines protect against the UK variant. Another study of the effectiveness of the same Pfizer-BioNTech vaccine against the B.1.1.7 variant confirmed this. Preliminary results presented in biorxiv, an open access preprint repository for the biological sciences, have shown Covaxin — an inactivated virus-based COVID-19 vaccine being developed by Bharat Biotech in collaboration with the Indian Council of Medical Research — to be effective against neutralizing the strain.
501.V2 (South Africa) variant
However, they are less effective against the South Africa variant, with Moderna reporting that the current vaccine produced only one-sixth of the antibodies in response to the South African variant compared with the original virus. It has launched a trial of a new vaccine to tackle the South African 501.V2 variant, also known as B.1.351. On February 17, 2021, Pfizer announced neutralization activity was reduced by two-thirds for the 501.V2 variant, while stating no claims about the efficacy of the vaccine in preventing illness for this variant could yet be made.
In January, Johnson & Johnson, which held trials for its Ad26.COV2.S vaccine in South Africa, reported the level of protection against moderate to severe COVID-19 infection was 72% in the United States and 57% in South Africa.
On February 6, 2021, the Financial Times reported that provisional trial data from a study undertaken by South Africa's University of the Witwatersrand in conjunction with Oxford University demonstrated reduced efficacy of the Oxford-AstraZeneca COVID-19 vaccine against the 501.V2 variant. The study found that in a sample size of 2,000, the AZD1222 vaccine afforded only "minimal protection" in all but the most severe cases of COVID-19. On February 7, 2021, the Minister for Health for South Africa suspended the planned deployment of around 1 million doses of the vaccine while they examine the data and await advice on how to proceed.
Commentaires