OPERATION WARP SPEED – WHAT? WHY? AND HOW?
Urgent and mandatory measures to contrast the COVID-19 spread
The Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2), is a viral strain of the SARS-related coronavirus species [1]. The World Health Organization (WHO) officially named Coronavirus Disease -19 (COVID-19) the syndrome caused by this virus. SARS-CoV-2 is transmitted through respiratory droplets or aerosols in case of prolonged exposure in an enclosed environment [2]. Although most patients develop mild symptoms [3] or are totally asymptomatic [4], severe cases of infection can lead to interstitial pneumonia, multiple organ failure, and eventually death [5]. As of the end of February 2021, over 110,000,000 COVID-19 cases have been reported all over the world, with over 2,500,000 deaths worldwide [6]. In the United States of America (USA), the situation is particularly severe with over 29,000,000 cases and over 500,000 death as of February 2021 [6].
COVID-19 outbreak developed in December 2019 in Wuhan, China, and rapidly spread all over the world. The epidemic was declared as a global pandemic by the WHO on 11 March 2020 [7]. This announcement and the declaration of a Public Health Emergency of International Concern (PHEIC) on January 30, 2020, lead to a strategy that encompassed patient isolation, active monitoring of contacts, and of suspected or confirmed cases, and public health quarantine [8]. Without vaccines or effective therapies available, physical control measures such as social distancing, wearing facemasks and quarantine have been the only extensively adopted interventions, leading to an urgent need for alternative healthcare delivery [9].
The pandemic itself and these protective actions aimed at defending public health came together with significant economic, social, and educational costs. An Italian observational study based on official governmental sources was published after the first pandemic wave in one of the most hit countries [10]. The total permanent productivity loss was estimated at around €300 million, and the temporary productivity loss was around €100 million [10]. Furthermore, a recent study tried to estimate the number of workers exposed to SARS-CoV2; approximately 10% and 18.4% of USA workers are employed in occupations where exposure to disease or infection occurs at least once per week or once per month respectively [11]. In this scenario, many people employed in jobs with frequent exposure to SARS-CoV-2 emphasize the importance of developing risk response plans for COVID-19 [11], such as the adoption of safety measures, as wearing personal protective equipment, and setting up large-scale vaccination campaigns. Based on the available data of SARS-CoV-2 transmissibility, it is estimated that more than 2/3 of the population must reach immunity to SARS-CoV-2 before the continuous transmission will conclude [12], [13].
Since this novel virus disseminates unpredictably, the above-cited traditional countermeasures such as hygiene, physical distancing, quarantine, and public lockdowns, resulted unsatisfactory as the pandemic is still ongoing, highlighting the urgent unmet need for preventing COVID-19 with mass vaccination.
Thus, based on epidemiological, clinical, and socio-economics data, emerged the urgency to develop an effective and safe vaccine to prevent COVID-19. To achieve the immunity of 2/3 of the entire population, it is obvious that the vaccines should be delivered on a large scale worldwide. A widely distributed vaccine would benefit both those who directly receive it (direct protection) and the who could not receive it (indirect or herd protection).
Operation warp speed: why and how.
The rapid and global diffusion of the SARS-CoV-2 virus, with its severe clinical and socio-economics burden, has generated an extraordinary focus on vaccine research and development [14]. This extraordinary scientific research goes along with an unprecedented amount of funding collection in a very short time [14].
The ongoing situation has led to the very fast development of vaccine candidates from academic researchers, and small or medium-sized biotech corporations, as well as large pharmaceutical companies.
In consideration of the severe worsening of the COVID-19 outbreak, on May 15, 2020, the former US President Donald Trump proclaimed a US public-private partnership, the OWSVI (Operation Warp Speed Vaccine Initiative), to hasten and support the development, production, and delivery of vaccines and treatments against COVID-19, and diagnostics tools [15]. The main and ambitious aim of the OWSVI was to make available hundreds of millions of doses of an effective and safe vaccine, essentially enough to vaccinate the entire USA population by January 2021 [15]. The OWSVI represents a milestone in pharmaceutical research and development, in particular, in the vaccine field, considering that only 15 vaccines were approved in the USA between 1995 and 2014, and just 1 out of 15 vaccines that enter phase II trials will never be commercialized. Since a vaccine is generally developed over decades [16], this initiative would represent an outstanding achievement. OWSVI works in association with the Department of Health and Human Services, the Centers for Disease Control and Prevention, the Food and Drug Administration (FDA), the National Institutes of Health, the Biomedical Advanced Research and Development Authority (BARDA), the Department of Defense, and other agencies, as well as private companies [17]. This public-private partnership was born to satisfy a known unmet need to reorganize the way the USA government typically supports drug development and vaccine distribution [18]. This initiative will allow mass production of multiple vaccines based on preliminary evidence, that is before completing clinical trials and FDA approvals. This way, when 1 or more of the tested vaccines show clinical efficacy, distribution can begin directly, without a delay linked to manufacturing facilities and delivery pathways [17]. Of course, it is expected that some of these vaccines will not be safe or effective. Indeed, most of the vaccines initially selected for the program will probably fail, and therefore the process of a COVID-19 vaccine production will certainly be much more expensive than what happens typically in a vaccine developmental program [17]. OWSVI has an official budget of $10 billion and can have access to supplementary funds through BARDA [15]. The concept of this initiative aimed to provide extensive research about COVID-19 prevention and treatment raised by the experience with previous serious epidemics, such as Zika [18], severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS) [19]. OWSVI supports the companies not just financially, but also technically to begin process development and industrial production as the vaccines are in preclinical or very early clinical developmental stage. OSWI also intervenes to ensure that all industrial procedures are properly set up in order to receive approval from the FDA at the end of phase 3 trials. The warp speed initiative also supports the construction or renovation of facilities, the adaptation of equipment, the selection and training of staff, the procurement of raw-material, the transfer and validation of technology, and purchase of vials, syringes, and needles for each vaccine candidate [18]. We aim to have stockpiled, at OWS’s expense, a few tens of millions of vaccine doses that could be swiftly deployed once FDA approval is obtained. The ultimate goal on which all these economic, technical and scientific projects converge is to have a provision of a few tens of millions of vaccine doses that could be rapidly distributed once FDA approval is obtained.
As of the end of 2020, eight companies were chosen for funding with $11 billion to accelerate the development and preparation for manufacturing their respective vaccine candidates [18]. The parallel studies for eight vaccines will increase the opportunities of delivering 300 million doses by the first half of 2021 [18].
The commercial investment strategy used by OWSVI is called “all in”, and is applied in a very early stage of vaccine development; this approach configures a high financial risk for both public and private investors, considering among all the products studied, more than 90% will probably fail [17]. These financial risks do not refer only to dollars, but also to the proactive building of manufacturing and delivery entities before completing the clinical studies [17]. In this context, the Bill and Melinda Gates Foundation has funded the build of different factories for 7 global candidate vaccines [17], Bill Gates in an interview pointed out the importance of not losing time founding several projects, even considering that among the 7 factories just a couple would give a tangible result [20]. To reduce the risk of failure, OWSI’s strategy is based on few principles. First of all, it is important to create a diverse project portfolio that comprises two vaccine candidates based on each of the four platform technologies [18]. This diversification reduces the risk of unsuccess as to safety, efficacy, industrial manufacturability, or scheduling factors, thus allowing the selection of the best vaccine platform for each subpopulation at risk for COVID-19, such as older adults, and healthcare workforce [18]. Furthermore, it is obvious that speed must not come at the expense of safety, efficacy, or product quality [18]. To achieve this goal, the development process, and manufacturing scale-up can be substantially accelerated by running all streams, fully resourced, in parallel. To achieve this, the development and manufacturing process can be significantly accelerated by running all fully resourceful processes in parallel [18]. This production and development approach goes along with a significative economic risk, as compared with the traditional sequential development methodology. To achieve this, the development and manufacturing process can be significantly accelerated by running all fully resourceful processes in parallel. To reach the set goals, the OWSI will highly enlarge the size of phase 3 trials, with 30,000 to 50,000 enrolled subjects in each; these so wide trials could benefit the research, by increasing the safety data collection for each studied vaccine [18].
Besides the prevention strategy through vaccination campaign, as there are no approved treatments for COVID-19, the Secretary of Health and Human Services at the beginning of the outbreak, also stated that there were the circumstances to justify the Emergency Use Authorizations (EUAs) for drugs and biological products, allowing a product to advance to clinical use once efficacy has been shown in phase II trials [21]. The EUAs have approved the use of different treatments, such as hydroxychloroquine and chloroquine, convalescent plasma, hyperimmune globulin, remdesivir, and Fresenius Propoven (propofol) 2% to treat COVID-19 [21]. Interestingly EUAs can be delivered by the FDA in a very rapid way, in fact the automatic authorization is realized whether the FDA does not oppose within 30 days of application. Moreover, the FDA can agree even more rapidly, whenever the review is complete [21]. As soon as the public health emergency will end, the marketing process of the studied drug or vaccine will require the completion of a complete investigational new drug application [17].
Lesson learned by the COVID-19 pandemic and future perspectives
Even before the COVID-19 outbreak, it was clear that drug research and development needed to proceed much faster to satisfy the many unmet needs in a multitude of healthcare settings. However, cultural heritage on one hand, and the lack of economic and technological resources on the other hand have very often put a stop to these new proposals. The serious health emergency still underway and the multitude of projects realized thanks to the enormous implementation of initiatives such as the OWS has shown the opposite.
Initiatives such as the widely described OWSI thought the world that the parallel processes of drug development and the removal of governance can speed up the vaccines and drugs research, production, and delivery. Obviously, the initiatives carried out during the pandemic must still be considered extraordinary, as these proceedings are necessarily associated with high financial risks, not affordable in everyday conditions.
However, we must keep all of the acquisitions learned while conducting the OWSI or the Pfizer's Lightspeed Project [22] for future use in serious conditions and for which there is no effective cure. In other words, we have seen that public and private entities can associate to speed up the urgent need of new treatment delivery, thus we hope that a similar need of urgency will be deployed for other vital health conditions [23]. Clinical and pharmacological researchers and developers are also leading clinical trial phases in new ways, merging trials, or providing adequate funding for overlapping enrollment for later-phase trials as earlier trials are still ongoing, to avoid wasting time [17].
Somehow the OWSI promised to do the impossible, or what was considered impossible. It has shown that whether a situation is considered enough hazardous for public health, programs that might otherwise take many years to achieve can be started and completed in few months, through the intervention of both public and private entities which deploy enormous resources.
It is true that the COVID-19 pandemic has disrupted healthcare and the global economy in a totally unexpected way, however, we must not forget that many other chronic clinical conditions have a significant impact on public health and the global economy. Suffice it to say that a highly disabling and widespread condition such as Alzheimer's disease is associated with high social costs, with estimated total healthcare costs for the treatment of Alzheimer disease in 2020 in the USA of $305 billion, with the cost expected to reach more than $1 trillion as of the population ages [24].
It is therefore clear that the lesson learned during the COVID-19 pandemic could lead to a new and more radical way of developing drugs for seriously disabling or fatal diseases such as neurodegenerative diseases or different types of neoplasms.
References
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