key: cord-0723625-iiess2fx authors: Jhaveri, Ravi title: The COVID-19 mRNA Vaccines and the Pandemic: Do They Represent the Beginning of the End or the End of the Beginning? date: 2021-01-22 journal: Clin Ther DOI: 10.1016/j.clinthera.2021.01.014 sha: 4cf40bd42bc538fb00798665266e3a93c55f8cd5 doc_id: 723625 cord_uid: iiess2fx In December 2020, the US Food and Drug Administration issued emergency use authorizations for two mRNA vaccines against COVID-19. These vaccines represent an incredible scientific achievement and a major step in efforts to bring the global pandemic to a close. However, these vaccines create many logistical challenges that limit just how far reaching their impact can be. This commentary reviews how these vaccines offer immunity, summarizes the phase 3 trial results and offers a discussion of the challenges that remain after these vaccines are introduced for widespread use. The COVID-19 pandemic has inflicted a heavy toll on the domestic and global population, with nearly 7% of the total US population having evidence of infection and over 80 million cases worldwide at the time of writing (1) . With the recent emergency use authorization (EUA) of 2 mRNA vaccine candidates (Moderna and Pfizer/BioNTech) by the US Food and Drug Administration, there is widespread hope of an inflection point in this pandemic that shifts from consecutive waves of increased cases to a gradual blunting of transmission that eventually leads to long-term control (2, 3) . This commentary will offer a brief summary of the pre-clinical and clinical development of the mRNA vaccines and a perspective on how these fit into our global public health goals for bringing this pandemic to a close. Widespread attention to cases of an unknown respiratory illness in Wuhan, China began in December 2019, with subsequent identification of the cause as a Betacoronavirus related to the SARS-CoV cause of the global 2003 outbreak (4) . Within a month, a full-length sequence of the dubbed SARS-CoV2 was available for global dissemination so researchers could begin to address the challenges of immunity. Within 5 days of the sequence being distributed, an mRNA vaccine candidate was produced using good manufacturing practices for early testing (5) . Within 66 days, a phase 1 human study was begun and just over 2 months later, a phase 2 human study was initiated (5) . The magnitude of this collaborative scientific achievement must be acknowledged. Historically, vaccine development to combat other viruses has occurred at a much slower pace. A vaccine candidate was not developed in 2003 with the initial SARS-CoV outbreak. With transmission localized primarily to 5 countries, suppression was achieved by contact tracing and isolation. Vaccine candidates for the 2009 H1N1 pandemic influenza strain were available for expedited testing in about 4 J o u r n a l P r e -p r o o f months after sequencing, capitalizing on the infrastructure for seasonal vaccine production (6, 7) . Full scale production and distribution occurred in an expedited process after an additional 6 months in November 2009. In contrast, the application of the mRNA platforms for successful vaccine delivery was novel. Proof of concept studies using mRNA platforms to rapidly develop possible vaccine candidates for pandemic influenza strains supported the idea that these could be produced in rapid response to a global outbreak (8) (9) (10) . Despite almost 3 decades of exploration with this technology, the discussions had by public and private partners about how mRNA vaccines could be optimized to address a global pandemic helped move things forward. With entirely new safety and efficacy data in an environment of significant antiscience sentiment and vaccine hesitancy, trust and confidence were paramount to achieving the EUA. To understand how the mRNA vaccines work, it is helpful to review a few key facts about the steps involved in viral infection and the subsequent immune response. First, mRNA is a natural set of instructions essential to the reproduction and life cycle of any virus, serving as a code for the proteins required for viral replication or assembly of new viral particles. The SARS-CoV2 mRNA vaccines encode for the spike protein, which is a fusion protein required for viral entry (11) . Prior studies evaluating immunity to SARS-and MERS-CoVs demonstrated that immunity to the spike protein was protective of clinical infection (12) . Second when a virus enters the host cell, fusion proteins undergo a key conformational change which facilitates the entry of genetic material to being the replication process (13) . Immunity to the "pre-fusion" conformation is protective to the host, but immunity to the "post-fusion" conformation offers no protection and may even be responsible for a dysregulated immune response (12) . A key step in the production of the mRNA vaccines was to introduce two proline J o u r n a l P r e -p r o o f substitutions to "lock" the spike protein in a "pre-fusion" conformation and prevent change to the "post-fusion" state so vaccination would offer the appropriate protection (5) . During natural infection, virus enters cells and produces the spike protein. These foreign proteins are recognized by antigen-presenting cells and used to activate T-and B-cells to general specific antibodies to protect against subsequent infection [ Figure 1 ]. In contract, mRNA vaccines directly introduce the genetic material to code to spike protein in antigen-presenting cells. The protein is produced and presented in the same way as natural infection. It is important to emphasize the unknowns that come with these vaccines. Currently approved vaccines for human use include formalin inactivated whole virus (e.g. Hepatitis A), live attenuated virus (e.g. MMR) or recombinant subunit vaccines (e.g. Hepatitis B). It is unclear just how long mRNA vaccine protection will last, but in theory, once anti-viral T-cells and memory B-cells are generated, immunity should be durable for many years. Within 2 months of sequence identification, a phase 1 human study was conducted with the Moderna vaccine. Fifteen participants were given 2 vaccine doses of 25 ug, 100 ug and 250 ug separated by 28 days (14) . In short, the 100ug dose offered the best combination of neutralizing antibody titers with acceptable reactogenicity. Doses of 50 ug and 100ug were used for the subsequent phase 2 study of 600 participants before progressing to the larger phase 3 trial (15) . In this study that formed the basis of the EUA, over 30,000 participants were enrolled in a placebo-controlled trial (15) . Randomized and blinded participants were given either 2 doses of either vaccine or saline injection, separated by 28 days, and followed for reactogenicity and clinical symptoms consistent with COVID-19. An interim follow-up period of 2 months was planned to evaluate for safety and efficacy. Given the racial and ethnic disparities noted in patients impacted by COVID-19, it is important to highlight that blacks made up 10% of study participants and 20% were self-identified as Latino (16) . By now, the J o u r n a l P r e -p r o o f interim results of this study have been well publicized [ Figure 2a ]. Vaccine efficacy was estimated to be 94.5% in all participants, which was consistent between those 18-65 y.o. and those >65 y.o. The Pfizer/BioNTech vaccine followed a similar path of development. Rodent and non-human primate studies demonstrated acceptable immunogenicity which was duplicated in human studies. A combined phase 1/2 study was conducted with 45 participants randomized into 3 dose groups, 12 receiving doses of 10 ug, 30 ug or 100 ug, and 3 participants in each group receiving placebo (17) . Local reactogenicity was common in all dosing groups, and the 30 ug dose offered the best combination of immunogenicity and tolerable reactogenicity. The 30 ug dose was used in the large phase 3 study with results now well publicized (18) . Over 37,000 randomized and blinded participants received 2 doses of either 30ug of vaccine or saline injection, administered 21 days apart. The racial and ethnic mix of participants in this trial was similar to the Moderna trial, and the efficacy was similar as well. The interim evaluation was planned to occur after 94 COVID-19 cases were identified among all participants. Estimated vaccine efficacy was noted to be 95%, with 4 cases found in the vaccine group and 90 in the placebo group. A more complete evaluation was presented to the FDA prior to issuing of the EUA, with 170 total COVID cases continuing to demonstrate the same 95% estimated efficacy [ Figure 2b ]. Efficacy among the cases identified in the vaccine group after one dose of vaccine resulted in an estimated efficacy against COVID of 52% after one dose of the Pfizer/BioNTech vaccine. While the efficacy of the 2 mRNA vaccines is very similar, the major difference lies in the product storage requirements and temperature stability. The Pfizer/BioNTech mRNA vaccine requires storage at -60° to-80°C, which requires either dry ice temporary storage or use of an "ultra-low" freezer (18) . After thawing, the vaccine is diluted in saline and should be administered within 6 hours. The requirement for either dry ice or "ultra-low" freezers severely limits the types of facilities where the cold chain can be maintained and the Pfizer/BioNTech vaccine administered. The Moderna mRNA vaccine is a bit more forgiving in its requirements. Long-term storage can be between -15° to -25°C, the J o u r n a l P r e -p r o o f temperature of a conventional freezer, and after thawing can be kept at 2° to 8°C for 30 days or room temperature if unopened for 12 hours and once opened discarded after 6 hours (15) . These more flexible storage requirements have allowed the Moderna product to be distributed to health departments, urgent care centers, clinical practices, and most importantly to rural entities where essential workers and residents of long-term care facilities may be immunized. Many have expressed concern at the speed of approval for both vaccines and whether safety requirements were fulfilled appropriately. While the EUA mechanism of approval does not convey licensure, it does facilitate use under a situation that is deemed to be emergent. Under the traditional vaccine approval process, the prolonged timeline is due to industry's hesitancy in investing in large-scale production without phase 2 and 3 efficacy studies and an almost guarantee of FDA licensure. Operation Warp Speed removed the financial risk of early large-scale production so this could take place coincident with phase 3 studies. With over 30,000 participants each, the size of the two phase 3 trials for these vaccines is comparable to the size of other phase 3 studies for currently licensed vaccines (19, 20) . The safety data generated from the Pfizer/BioNTech and Moderna phase 3 studies is equivalent to the enrollments for traditional phase 3 vaccine licensing requirements. However, ongoing monitoring for rare adverse events will need to be conducted under the terms of the EUA and as traditional licensure is likely pursued. The development of these first vaccines is an incredible achievement and offers public health officials and the medical community cause for some optimism and another tool in a valued armamentarium against SARS-CoV2. However, this optimism needs to be tempered with acknowledgement of many factors that may limit the impact these mRNA vaccines. As was already mentioned, the cold chain storage requirements for both products will restrict where and who can administer vaccines. The Pfizer/BioNTech vaccine lends itself to administration in hospitals and large healthcare facilities with ready access to "ultra-low" freezers or dry ice. The more flexible storage requirements of the Moderna vaccine have facilitated its use in public health and community settings to vaccinate the elderly and residents of congregate facilities. The considerable experience vaccinating adult and pediatric inpatients and specialty clinic outpatients with seasonal influenza and pneumococcal vaccines could be leveraged to do the same for COVID vaccination of those receiving acute and subspecialty care in these settings (21, 22) . Workflows for immunizing children and adults who do not access the healthcare system regularly will need to be developed. There are opportunities for public-private partnerships with commercial pharmacies and educational facilities to increase uptake. Other vaccine candidates that require only one dose and can be stored without freezing will further facilitate expanded access. While there were important attempts to achieve racial and ethnic diversity in phase 3 trial enrollment, several important subpopulations were not included in study enrollment. Pregnant women make up a significant portion of the healthcare workforce who are among the highest priority for receiving vaccine. Despite the fact that no research was done to examine mRNA vaccine safety and efficacy in pregnant women, the Advisory Committee for Immunization Practice COVID task force (25) . Any long-term strategy for control of COVID-19 will need to include plans for universal vaccination of children with involvement of pediatric health care providers(26). One also needs to consider many of the challenges to the logistics of trying to vaccinate most of the domestic and global population. Moderna has never had an approved vaccine before, and neither has BioNTech. Both have produced other mRNA products on a small scale, but nowhere near the hundreds of millions of doses that will be required. It is not surprising that there have been shortfalls in the number of expected doses ready to be administered in the early weeks after the EUAs were granted(27). Our U.S. system falls short with reliably delivering vaccines. While routine childhood vaccination rates are greater than 90%, these are given to an annual birth cohort of less than 4 million children(28). While seasonal influenza vaccine is recommended for everyone 6 months and older, even with public health education efforts to encourage people to get vaccinated, rates hover around 50% (29) . The highest rate of seasonal influenza uptake, approaching 75%, in children under 5 years of age, is likely the result of receipt of routine childcare in a medical home. A more sobering uptake of 38% in adults years results from the absence of a medical home and receipt in an array of workplace, public health and retail sources. Given the increased transmissibility of the SARS-CoV2 virus, estimates have suggested that we will need to vaccinate about 70-80% of the population in order to halt the spread of the virus(30). This will take several different vaccine products saturating every possible outlet for delivery plus new and creative ways to administer vaccines well beyond what has been done previously. This will also require addressing widespread apprehension and vaccine hesitancy among the general population and outreach to disadvantaged racial and ethnic minority groups (31) . In the meantime, the need for universal masking, rigorous hand hygiene and social distancing will need to remain in place as the primary means of ongoing prevention. These mRNA vaccines offer little promise to prevent COVID-19 infections in resource-limited settings. Affluent countries have purchased advance access to hundreds of millions of doses as they are being produced for the next several years (32) . Estimates are that supply would not be available until global settings, and this is why the World Health Organization has set up a program called COVAX, which is designed to ensure that affordable COVID-19 vaccine candidates are secured for distribution in resource-limited settings (33) . The vaccine candidate from AstraZeneca and Oxford that just received EUA in the UK has been targeted for resource-limited settings with an anticipated cost of $3 per dose (34) . The specifics of this vaccine are quite distinct from the mRNA vaccines and outside of scope of this discussion. While the estimated vaccine efficacy is only about 70%, it still offers a much needed option for the UK and for the COVAX global initiative to deliver hope to resource-limited countries (35) . The impact of the pandemic in these settings has been devastating, so access to a vaccine to help them manage the cases for the global population will be critical. The two COVID-19 mRNA vaccines represent an incredible scientific achievement and offer hope to reduce the devastating impact that COVID-19 has had both domestically and internationally. Enthusiasm for their potential should be tempered by the operational aspects of uptake and delivery, all of which will be required to reduce the clinical and societal morbidity and mortality. Over the next several months and years, as more vaccine products receive regulatory approval and become available, the challenges of supply and need will hopefully be tempered along with the spread of SARS-CoV-2. to health care worker colleagues who continue to work under challenging circumstances to provide care to those in need in this pandemic. COVID-19 Global Cases Data Center FDA Takes Key Action in Fight Against COVID-19 By Issuing Emergency Use Authorization for First COVID-19 Vaccine FDA Takes Additional Action in Fight Against COVID-19 By Issuing Emergency Use Authorization for Second COVID-19 Vaccine A Novel Coronavirus from Patients with Pneumonia in China mRNA vaccine design enabled by prototype pathogen preparedness Phase 2 assessment of the safety and immunogenicity of two inactivated pandemic monovalent H1N1 vaccines in adults as a component of the U.S. pandemic preparedness plan in 2009 Clinical and immune responses to inactivated influenza A(H1N1)pdm09 vaccine in children Novel vaccine technologies for the 21st century Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies Ready, set, fuse! The coronavirus spike protein and acquisition of fusion competence Pre-fusion structure of a human coronavirus spike protein Activation of paramyxovirus membrane fusion and virus entry An mRNA Vaccine against SARS-CoV-2 -Preliminary Report FDA Briefing Document-Moderna COVID-19 Vaccine The Disproportionate Impact of COVID-19 on Racial and Ethnic Minorities in the United States Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults FDA Briefing Document-Pfizer-BioNTech COVID-19 Vaccine Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine Inpatient computer-based standing orders vs physician reminders to increase influenza and pneumococcal vaccination rates: a randomized trial Centers for Disease Control and Prevention. Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines Currently Authorized in the United States Changing Age Distribution of the COVID-19 Pandemic -United States Herd immunity -estimating the level required to halt the COVID-19 epidemics in affected countries Trusted Messengers, Trusted Messages': How To Overcome Vaccine Hesitancy. National Public Radio Poor Countries Fall Behind In Race To Reserve COVID-19 Vaccine. Goats and Soda COVAX: Working for global equitable access to COVID-19 vaccines 2020 As COVID-19 vaccines emerge, a global waiting game begins Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised My thanks to Andi Shane MD, MPH for her thoughtful and detailed input on the content of this commentary, and Taylor Heald-Sargent MD, PhD for her input on content of the figures. My best wishes