key: cord-0868246-xb4e9hek authors: Rolak, Stacey; Hayney, Mary S.; Farraye, Francis A.; Temte, Jonathan L.; Caldera, Freddy title: What Gastroenterologists Should Know About COVID-19 Vaccines date: 2021-02-03 journal: Clin Gastroenterol Hepatol DOI: 10.1016/j.cgh.2021.01.001 sha: 557392fb320a73a73f74d5dbabed5be10ea8ffe1 doc_id: 868246 cord_uid: xb4e9hek nan late December of 2019, cases of pneumonia caused by betacoronavirus SARS-CoV-2, closely related to SARS-CoV, were reported in the city of Wuhan, China. SARS-CoV-2 has resulted in a worldwide pandemic that continues to surge throughout the United States. Two vaccines for SARS-CoV-2 (the virus that causes COVID-19) are now available under emergency use authorization (EUA). An EUA was issued for the Pfizer-BioNTech COVID-19 vaccine on December 11, 2020, and another EUA was issued for the Moderna COVID-19 vaccine on December 18, 2020. Development of a coronavirus vaccine is not new. Vaccines against SARS-CoV were developed and tested in phase I trials in the 2000s, but development halted because of the disappearance of the virus. 1 Similarly, vaccines against Middle Eastern respiratory syndrome are under active development, but not at an accelerated pace, because of extremely low prevalence of the virus. The information gained from preclinical studies with SARS-CoV and Middle Eastern respiratory syndrome laid the groundwork to identify the spike protein as a target for development of a vaccine against SARS-CoV-2 at an early stage. 1 In response to the pandemic, vaccine development has moved expeditiously with more than 200 COVID-19 vaccine candidates currently under development or in clinical trials. 2 These candidate vaccines are based on traditional approaches (inactivated or live attenuated vaccines), methods that have resulted in newly licensed vaccines (recombinant protein vaccine and vectored vaccines), and methods that have not resulted in a licensed vaccine (RNA and DNA vaccines). 1 Vectored vaccines incorporate 1 or more viral genes into the genome of viral vectors. These vectors are used to transport genetic material to host cells for transcription and expression of the desired coronavirus antigen. 1 The Pfizer-BioNTech and Moderna vaccines use mRNA platforms. Preliminarily, these vaccines are reported to be more than 90% efficacious at prevention of symptomatic infections. 3 The vaccine antigen is coded by mRNA, which is protected by a lipoprotein coat. On vaccine administration, cells pick up the mRNA and translate it into a protein (in this case, the SARS-CoV-2 spike protein). The immune system then mounts a response to that protein. Although no mRNA vaccines against other infectious agents are presently available, mRNA vaccines have shown great promise, and in recent years many are in development to treat cancer and other infectious disease, such as Zika virus and cytomegalovirus. 1 Widespread public acceptance and uptake of COVID-19 vaccines, in addition to concomitant prevention strategies, will be imperative in containing the spread of disease. Unfortunately, the general public's confidence in a COVID-19 vaccine under the US government's Operation Warp Speed (OWS) initiative has been clouded in an environment of political polarization and general mistrust of public health and governmental agencies. One survey found that having a vaccine available under a Food and Drug Administration (FDA) EUA was associated with a lower probability of willingness to get vaccinated, compared with standard FDA licensure. 4 Vaccine hesitancy in adults is a complex issue and in general, there are few strategies to ameliorate this. Increasing uptake of vaccines is important, especially in the case of this pandemic, to achieve herd immunity and protect the general population. The Centers for Disease Control and Prevention's Vaccinate with Confidence campaign's strategic framework has been customized to increase support for COVID-19 vaccinations. 4 This campaign centers around the principles of reinforcing trust using transparent communication about the process of licensing, and safety of, vaccines; empowering health care providers to discuss vaccines with their patients by providing simple talking points; and engaging communities and individuals to explore service delivery strategies for vaccine distribution. 5 print & web 4C=FPO 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 How Have COVID19 Vaccines Been Developed, How Will They Receive EUA/Approval Multiple vaccines for COVID-19 are being developed and tested on an unprecedented timeline. There are more than 200 vaccine candidates currently in development against SARS-CoV-2, and there are several candidate vaccines in the United States that are in active phase III clinical trials. 2 An overview of the typical timeline for vaccine development is illustrated in Figure 1 . 6 Vaccine development is a complex, expensive, and lengthy process, with the typical timeline from preclinical studies to final licensure often ranging between 10 and 15 years. 7 The general public has voiced anxiety over the expedited timeline for vaccine development under OWS, with concern that there is not strict adherence to the regulatory standards for approval. 8 OWS, announced on May 15, 2020, is an initiative to control the COVID-19 pandemic by advancing the development, manufacturing, and distribution of vaccines, therapeutics, and diagnostics. OWS is a partnership of the Department of Health and Human Services, the Department of Defense, and the private sector. These agencies are providing funding and coordinated government support to accelerate vaccine development while still maintaining standards for safety and efficacy. OWS has worked with vaccine developers to enable, accelerate, and harmonize vaccine protocols of highly powered efficacy trials (Figure 1 ). Rather than eliminating steps from the traditional vaccine development timeline, trial phases are being combined and are proceeding simultaneously to expedite development. 6 Although vaccine development has been accelerated, no steps in the typical vaccine development process have been skipped. Leadership of the FDA have emphasized that candidate vaccines are being reviewed according to their rigorous established legal and regulatory standards. 9 Vaccine efficacy and safety have been promising in several candidates to date. The primary end point for all vaccines currently in phase III clinical trials is COVID-19 symptomatic disease, as illustrated in Table 1 . The Advisory Committee on Immunization Practices (ACIP) has provided interim recommendations for the currently available COVID-19 vaccines, as outlined in Table 2 . 10 These considerations are specific to the Pfizer and Moderna mRNA vaccines, which are available for use under EUA. An EUA differs from vaccine licensure. An EUA allows use of unapproved medical products to diagnose, treat, or prevent serious or life-threatening diseases or conditions in response to a declared public health emergency for which there are no adequate, approved, and available alternatives. The issuance of an EUA requires a determination by the FDA that the vaccine's benefits outweigh its risks based on data from at least 1 well-designed phase III clinical trial that demonstrates the vaccine's safety and efficacy in a compelling manner. The FDA expects manufacturers who receive an EUA to continue their studies to obtain comprehensive safety and effectiveness information and pursue final licensure of their product. 11, 12 An EUA still requires review of extensive safety and efficacy data from phases I 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 and II of vaccine studies, with an expectation that phase III data include a median follow-up of at least 2 months for vaccine recipients. This 2-month timeframe was selected because adverse events considered potentially linked to vaccination typically start within 6 weeks of vaccine receipt. 11 Vaccines made available with EUA will have met this safety requirement. Furthermore, longterm safety data will continue to be collected for those in clinical trials and those who receive the vaccine under an EUA with safety monitoring systems, such as Vaccine Adverse Event Reporting System, the Vaccine Safety Datalink, and Clinical Immunization Safety Assessment and safety review by the Institute of Medicine. 13 The FDA has indicated that any decision about vaccine EUA or licensures will be discussed by the ACIP. 9 The ACIP is a group that provides advice to the Centers for Disease Control and Prevention Director and the Secretary of the Department of Health and Human Services. Because of their standing as a federal advisory committee, they hold open meetings with public involvement, and report their recommendations transparently. In addition to the 15 voting members, the committee has ex officio members and representation from liaison organizations, such as the American Medical Association and the American Academy of Pediatrics. 14 Although the ACIP generally holds meetings 3 times per year, during which they develop the childhood and adult immunization schedules and make recommendations for vaccine use in the United States, they have been meeting monthly to prepare recommendations for COVID-19 vaccines. 14 The ACIP convened and recommended the Pfizer and Moderna vaccines before the issuance of an EUA by the FDA. With vaccines available, several considerations need to be taken to ensure fair and equitable access to this limited resource. The ACIP has provided recommendations on which groups should be prioritized for the earliest allocations of the vaccine. These recommendations were centered around 4 ethical principles: (1) maximize benefits and minimize harms, (2) promote justice, (3) mitigate health inequities, and (4) promote transparency. 15 A phased allocation of vaccines is planned. On December 2, 2020, the ACIP voted and stated that when a COVID-19 vaccine is authorized by the FDA and recommended by the ACIP, vaccination in the initial phase of the COVID-19 vaccination program (Phase 1a) should be offered to health care personnel and residents of long-term care facilities. This will be followed by those in phase 1b, which consists of frontline essential workers and persons age 75 years and older. Phase 1c will include persons age 65-74 years and those age 16-64 with high-risk conditions. Finally, phase 2 will include all other healthy adults. The COVID-19 vaccines that are first made available to health care personnel and residents of long-term care facilities, followed by other individuals at high risk for complications of COVID-19, have met rigorous efficacy and safety standards with no shortcuts taken in their development. It is essential to actively address the spread of distrust and misinformation surrounding vaccines for COVID-19. Clinicians must feel comfortable educating patients that all of the appropriate steps are being taken to ensure that the COVID-19 vaccine is safe and effective, to help dispel vaccine hesitancy among patients. SARS-CoV-2 vaccines in development Draft landscape of COVID-19 candidate vaccines Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine Factors associated with US adults' likelihood of accepting COVID-19 vaccination Vaccinate with confidence for COVID-19 vaccines. Center for Disease Control and Prevention Developing safe and effective Covid vaccines: Operation Warp Speed's strategy and approach Developing Covid-19 vaccines at pandemic speed Unwavering regulatory safeguards for COVID-19 vaccines Development and licensure of vaccines to prevent COVID-19. US Food and Drug Administration. Guidance for Industry The Advisory Committee on Immunization Practices' Interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine-United States Emergency use authorization of Covid vaccines: safety and efficacy follow-up considerations Emergency use authorization for vaccines explained Postapproval vaccine safety surveillance for COVID-19 vaccines in the US History and evolution of the advisory committee on immunization practices-United States The Advisory Committee on Immunization Practices' ethical principles for allocating initial supplies of COVID-19 vaccine-United States The authors thank the Advisory Committee on Immunization Practices and the COVID-19 Vaccine Workgroup for all the work they have done in providing recommendations for safe, effective delivery of a COVID-19 vaccine These authors disclose the following: Mary S. Hayney is a consultant for GSK Vaccines and Seqirus; and has received research support from Takeda Pharmaceuticals and Sanofi. Francis A. Farraye is a consultant for BMS, Braintree Labs, Gilead, GSK, Innovation Pharmaceuticals, Janssen, Pfizer, and Sebela; and sits on a DSMB for Lilly and Theravance. Jonathan L. Temte is on the advisory board of Elsevier Practice Update Primary Care; and has received research funding from Quidel. Freddy Caldera has received research support from Takeda Pharmaceuticals and Sanofi; and has been a consultant for Takeda, Arena Pharmaceuticals, GSK, and Celgene. Stacey Rolak discloses no conflicts