Understanding COVID-19 Vaccines and Their Development.

Abstract

By May 15, 2020, 65 days after the World Health Organization (WHO) declared the novel coronavirus disease 2019 (COVID-19) pandemic, 4.2 million individuals were confirmed as being infected with the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and 294,000 people had died from the disease1. These numbers are almost certainly an underestimation of the true morbidity and mortality of the disease to this point. From the beginning of this public health crisis, attention has focused on the development of vaccines against SARS-CoV-2. Many believe that immunization is the key advance in the war against COVID-19 and that control of SARS-CoV-2 allowing approximations of pre-pandemic social conditions will not be possible without a viable vaccine2. Until a viable vaccine is developed, extensive diagnostic testing, quarantining, and social distancing are the only control methods that we have3. This article was written for musculoskeletal physicians and scientists without immunology backgrounds. It seeks to provide a concise but comprehensive understanding of vaccine development with a special emphasis on efforts to establish immunization directed against SARS-CoV-2. This will help to inform readers of the challenges to be hurdled and allow them to track milestones reached as the global community labors toward an effective vaccine. In-depth reviews of complex immunology topics, viral epidemiology, the myriad historic aspects of vaccine development, and the economics of developing and utilizing different types of vaccines are beyond the scope of this work. Background SARS-CoV-2 To understand the process of vaccine development, one must start with a basic understanding of the pathogen against which it will be directed. SARS-CoV-2 is a beta coronavirus4. The virus has been found to be similar to another coronavirus whose usual hosts are bats. It is believed that wild animals being sold at a market in Wuhan, Hubei Province, the People’s Republic of China, led to the transmission of SARS-CoV-2 to humans5. Members of the Coronaviridae family have a positive-sense, single-stranded RNA ([+]ssRNA) genome6. The (+)ssRNA can serve as messenger RNA (mRNA) in the host cell, allowing utilization of host ribosomal machinery to translate viral proteins. This coronavirus genome is highly conserved6. The first gene (open reading frame [ORF]1a and ORF1b) is involved in replication and transcription. Subsequent genes are related to structural proteins (Fig. 1). The spike protein (S) has an exposed location on the virion and is necessary for entry into the cell. Blocking of the spike protein epitopes that interact with angiotensin-converting enzyme 2 (ACE2), the host cellular receptor for SARS-CoV-2, should lead to neutralization (Fig. 2). ACE2 degrades angiotensin II (AngII), downregulating the renin-angiotensin-aldosterone system. ACE2 is distinct from the angiotensin type-I receptor, which leads to activating signal transduction by AngII7.Fig. 1: Illustration of the SARS-CoV-2 genome showing expressed structural component proteins and their location within the virion. The open reading frame (ORF) codes for nonstructural viral proteins participating in viral genome replication, transcription, and protein processing. The spike protein (S) binds to the ACE2 receptor, allowing virus entry into host cells. The envelope protein (E) has been found to bind to host gene regulatory proteins and putatively influences host cell gene expression. The membrane protein (M) seems to cooperate with S during binding and entry into the cell. The nucleocapsid protein (N) coils the viral mRNA inside the viral particle, organizing and protecting it.Fig. 2: SARS-CoV-2 virion entry into the host cell. The virus enters the host cell via the S protein interacting with ACE2. It is important to generate antibodies to the S protein rather than ACE2. This allows ACE2 to remain open to receive the host ligand and to avoid the possibility that the blocking antibody interferes with its normal physiologic function.COVID-19 is usually characterized by fever, cough, dyspnea, fatigue, and sore throat. Radiographic findings have demonstrated pneumonia with infiltrates on chest imaging8. Typically, radiographic changes appear on presentation. In Wuhan, 76% of diagnosed patients demonstrated changes on chest radiographs9. It is unknown whether radiographic changes arise prior to the onset of symptoms. Currently, there are no known curative treatments for COVID-19. Treatment is centered around supportive care while the afflicted individual clears the infection. In some cases, supplemental oxygen needs to be administered to help those with the associated pneumonia to maintain their oxygen saturation. Severe cases may benefit from antiviral medications, dexamethasone10, and ventilatory support with or without extracorporeal membrane oxygenation11,12. In March 2020, the WHO estimated the global mortality rate for those confirmed to have a SARS-CoV-2 infection to be 4.3%, although this varies by region13. Vaccines Vaccines meet the definition of a drug because they are substances other than food used in the prevention, diagnosis, alleviation, treatment, or cure of a disease14. They are administered to healthy individuals to prevent diseases caused by infectious agents to which they might be exposed in the future or, in some cases, to which they have been recently exposed. Immunization is the process of presenting antigens to a live host to induce an immune response. Vaccines can be utilized therapeutically and prophylactically. Most vaccines are developed as prophylaxis against infection. A primary goal of prophylaxis is to generate neutralizing antibodies that prevent viral entry into cells. However, in some cases, vaccines can be administered for short-term protection. This short-term protection is termed passive immunization. A smaller proportion of vaccines are developed for the therapeutic treatment of infections that have already become initiated. An example of this is the vaccine used after exposure to rabies15. Epidemiology of Infectious Disease and Vaccination During infectious disease outbreaks, vaccines have the ability to break chains of transmission, drastically slowing the propagation of infection and eventually eradicating the disease. The vast majority of individuals in modernized societies are immunized against a host of pathogens as children. This global public health effort has resulted in the worldwide elimination of smallpox16 and substantial progress toward the elimination of polio17. These accomplishments required concerted international efforts that were sustained over many decades. The epidemiologic dynamics of vaccination, especially in a population with a disease presence (either endemic or epidemic), can be described mathematically. The basic reproduction number (R0) is the intrinsic measure of transmissibility of a pathogen. It describes the mean number of secondary infections resulting from a single infection within a fully susceptible population (Fig. 3). For SARS-CoV-2, R0 has been estimated to be between 2 and 318.Fig. 3: Illustration of the basic reproduction number (R0) values for representative infectious diseases, demonstrating increasing infectivity with increasing values of R0. HIV = human immunodeficiency virus.Once substantial immunity, through either vaccination or natural exposure to the disease, starts to be established in the population, R0 becomes a less accurate measure of transmissibility, and a second number, the effective reproduction number (Re), becomes more representative of transmissibility. Re represents the actual number of transmissions per infection. For an explanation of how these numbers are calculated and their effect on viral epidemiology (Fig. 4), please see Appendix I.Fig. 4: The relationship between the basic reproduction number (R0) and the effective reproduction number (Re) of a pathogen. Re changes based on the percentage of the population that is immune, demonstrated by the different lines on the chart. For a disease with an R0 of 3.5, immunization of 70% of the population will be necessary to bring Re below 1.0. This can be compared with an immunization level of only 50% needed to bring Re below 1.0 for a disease with an R0 of 2.0. If Re, a measure of disease transmissibility, is <1, a disease outbreak will end without further measures being taken.Herd Immunity Herd immunity is a condition achieved in a population when the indirect protection of susceptible individuals against a specific pathogen is conferred by immune individuals. In effect, those with immunity within a population shield those without immunity from transmission, thereby limiting the spread of the disease19 (Fig. 5). A further explanation of how R0 and Re affect herd immunity (Figs. 6 and 7) is found in Appendix II.Fig. 5: Illustration demonstrating herd immunity. The spread of a hypothetical illness within a population is shown under 3 different conditions. The top row is a time early after the introduction of the pathogen within a population. The second row represents 1 replication cycle and the third row represents 2 replication cycles following the time represented in the top row. In the left column, the population is fully susceptible (no naturally acquired immunity or immunity through vaccination) to the pathogen. The middle column represents an intermediate state between full susceptibility and achievement of the herd immunity threshold (Pcrit). The column on the right represents how spread is hindered in a population that has already achieved Pcrit.Fig. 6: The relationship between the basic reproduction number of a virus, R0, and the proportion of the population that needs to be immunized to enter into a state in which herd immunity takes effect, Pcrit. R0 is unitless and Pcrit is measured as the percentage of the population. The slope of the curve is greatest between R0 values of 1 and 4, indicating that a large increase in the proportion of immune individuals within the population is needed to achieve Pcrit for an infectious disease with an R0 that is just slightly larger than another. The estimated R0 for SARS-CoV-2 is between 2 and 3, which is demarcated in the area between the dotted lines on the graph. This R0 range indicates that the percentage of the population that needs to become immune to reach Pcrit, either through infection or vaccination, is between 50% and 66.7%.Fig. 7: Vaccination affects the achievement of herd immunity. This graph shows vaccination affecting herd immunity to diphtheria. Diphtheria-tetanus-pertussis (DTP3) immunization coverage is expressed as a percentage of the population from 1982 to 2016. The red line on this graph represents the number of diphtheria cases reported worldwide by year. The blue line represents the immunization coverage as a percentage of the population by year. The dashed orange line represents the herd immunity threshold (Pcrit) for diphtheria assuming that it has an R0 of 6. The graph demonstrates how achieving immunization levels just slightly above Pcrit can drive the number of cases down to just a few thousand per year.SARS-CoV-2 Vaccines Under Development It is through recombinant nucleic acid technology that most efforts against COVID-19 are progressing. Theoretically, vaccines using recombinant nucleic acid technology can be developed and, therefore, deployed more quickly than those using more traditional means. However, a few are based on immunologic techniques used widely in the mid-twentieth century for the development of vaccines used in standard childhood immunization schedules. Table I summarizes the types of vaccines as well as their advantages and disadvantages. By June 2, 2020, >130 candidate vaccines targeting SARS-CoV-2 were under development worldwide according to the WHO20. Ten of these candidate vaccines have entered into human trials. Table II summarizes the SARS-CoV-2 vaccines currently in development. TABLE I - Advantages and Disadvantages of Different Vaccine Types* Type of Vaccine Example Vaccine(s) Advantages Disadvantages Potential Solutions to Development Problems Attenuated Sabin polio (host-range mutant) Smallpox (Jennerian method) Reliable Confer both humoral and cell-mediated immunity Limited need for booster doses Relatively inexpensive technology May yield less protective mutant viruses if passages are performed in non-human cell lines63 Can cause disease in immunocompromised individuals Enhanced storage and maintenance requirements (e.g., refrigeration, culture media) Inactivated Typhoid Salk polio Rabies Influenza Relatively fast Easy to scale up Relatively inexpensive development Alternate routes of administration (e.g., oral) Inactivation can sometimes damage key epitopes Can still theoretically cause disease (if not fully inactivated) Labor-intensive process to ensure no viable virion remains after inactivation Greater amounts of inoculum required to achieve immunity Immune response is less durable, requiring booster doses64 Titration of inactivation methods to prevent overtreatment, maintaining key epitopes Subunit Hepatitis B surface antigen Safe Easy to use Requires large amounts of isolated antigen Immunopotentiation2,65 Recombinant technology has made large-scale production possible Adjuvants can be added to vaccine preparations66 mRNA29 HIV† Zika† Influenza† Rabies† Can replicate using host machinery Highly potent Relatively fast Easy to scale up • Relative low cost of manufacturing Safe Confer both humoral and cell-mediated immunity dsRNA byproducts of production are PAMPs‡ and lead to immune recognition and degradation29 Inefficient delivery to target cells Instability of mRNA Modified nucleosides avoid host immune recognition Purification to eliminate dsRNA Multiple delivery methods devised to improve efficiency Inclusion of upstream and downstream untranslated sequences improves stability of mRNA DNA plasmid Prostate cancer† Melanoma† Can replicate using host machinery Highly potent Relatively fast Easy to scale up • Safe Confer both humoral and cell-mediated immunity Inefficient delivery to target cells Coupled treatments (e.g., electroporation) to improve DNA plasmid entry into human cells34 and enhance immune response31-33 Vector-based recombinant (e.g., adenovirus vector) Malaria† HIV† Ebola (in development) Confer both humoral and cell-mediated immunity Enter host cells via ubiquitously expressed cell surface receptors Can incorporate additional transgenes for biological adjuvants37,67 Highly potent Relatively fast Easy to scale up in low-resource settings68 Safe Easier, alternate routes of administration favoring IgA production (e.g., oral, intranasal)69,70 Vector immunity due to host recognition of adenovirus71 If replication-competent viral vectors are utilized, could cause adenovirus infection Administration via mucosa may require dose escalation Repeated immunizations can diminish neutralizing antibodies to adenovirus vectors, thereby decreasing vector immunity71 Utilize different adenovirus strains to evade vector immunity70,72,73 Utilize chimpanzee adenovirus vectors to evade vector immunity due to highly conserved genome74 Use of replication-competent viral vectors can boost immunogenicity *HIV = human immunodeficiency virus, dsRNA = double-stranded RNA, PAMP = pathogen-associated molecular pattern, and IgA = immunoglobulin A.†In trials.‡These are present and invariant in the pathogen but not in the potential host organism; PAMPs allow early recognition and immune activation by the host organism75. TABLE II - SARS-CoV-2 Candidate Vaccines Currently in Clinical Development* Vaccine Type Clinical Phase of Development Trial No. (Location) Chimpanzee adenovirus vector-based (nonreplicating) Phase 2b/3 2020-001228-32 (EU) mRNA (lipid nanoparticle encapsulated) Phase 2: scheduled to conclude September 2021 NCT04405076 (USA) Adenovirus-5 vector-based (nonreplicating) Phase 2: scheduled to conclude January 2021 ChiCTR2000031781 (China) Subunit (recombinant spike protein) Phase 1 and 2: scheduled to conclude July 2021 NCT04368988 (USA) mRNA (lipid nanoparticle encapsulated) Phase 1 and 2: scheduled to conclude June 2021 NCT04368728 (USA), 2020-001038-36 (EU) Inactivated with aluminum adjuvant Phase 1 and 2: scheduled to conclude July/August 2020 NCT04383574 (USA), NCT04352608 (USA) Inactivated Phase 1 and 2: scheduled to conclude November 2021 ChiCTR2000031809 (China) Inactivated Phase 1 and 2: scheduled to conclude November 2021 ChiCTR2000032459 (China) DNA plasmid (with electroporation) Phase 1: scheduled to conclude July 2021 NCT04336410 (USA) Inactivated Phase 1 China *As of June 2, 2020. Attenuated Vaccines Vaccines that use a weakened but viable form of the pathogen to establish an immune response are termed attenuated vaccines. The establishment of attenuated strains is an empiric rather than a designed process, the duration of which is influenced by the scale of the process and the time necessary to complete the passage of the virus in the cell culture. In rare cases, the attenuated variant can revert to a virulent form, resulting in the establishment of the disease in the immunized cohort. There are 4 different types of attenuated vaccines. At least 3 different groups are seeking to develop attenuated vaccines against COVID-1920. The most common form of an attenuated vaccine is the host range mutant. This type is usually achieved by the passage of the virus in the cell culture to generate nonvirulent mutants. Over multiple passages, the host range mutant acquires mutations, rendering it harmless while retaining the necessary antigens to generate immunity. The second type is naturally attenuated. This method requires empiric identification and recovery of variant or minimally variant strains during periods of outbreak21. The third type of attenuated vaccine is the temperature-sensitive mutant. This method isolates mutants that grow poorly at temperatures of >37°C. Examples include influenza strains that can be passaged at 25°C (which is the temperature found at the upper respiratory tract) but become nonvirulent at the core body temperature or above22. The last type of attenuated vaccine, termed Jennerian, is not being attempted in the current COVID-19 vaccine development efforts. Inactivated Vaccine Inactivated-virus vaccine generation requires large amounts of viral particles to be grown in culture, separated, and then rendered noninfectious by either chemical or physical means23 (Fig. 8-A). The purpose of inactivation is to render the virus nonvirulent without altering the epitopes to which an immune response is generated. Both chemical and physical means can inactivate virus particles24. A balance needs to be achieved in the preparation of inactivated vaccines. Overtreatment will lead to excess denaturation and loss of key epitopes, leading to a neutralizing antibody response that is suboptimal and poorly protective upon challenge with a live virus25,26. However, if complete inactivation does not occur, outbreaks of the disease can occur from the vaccination itself27,28.Fig. 8: Figs. 8-A through 8-E Illustrations depicting some vaccine types that are being developed against SARS-CoV-2. Fig. 8-A Inactivated vaccine: viral particles are grown in quantity and then rendered replication-incompetent through physical or chemical means. The injection of inactivated viral particles allows the generation of an immune response without risk of infection. Fig. 8-B Subunit vaccine: viral proteins are collected and purified. These purified proteins are then injected into patients to be vaccinated. The proteins are processed by the host cells and the antigens are presented so that an antibody response is generated. Fig. 8-C mRNA vaccine: mRNA encoding the viral S protein is amplified in the laboratory and is packaged using technology such as lipid nanoparticles. These mRNA molecules are transcribed and are translated into viral proteins using host machinery, and the antigens are presented so that an antibody response is generated. Fig. 8-D DNA plasmid vaccine: complementary DNA (cDNA) for the viral S protein is incorporated into a DNA plasmid. This plasmid enters host cells, where translation and transcription machinery generates viral proteins. These viral proteins generate an antibody response. Fig. 8-E Adenovirus vector-based vaccine: the gene for the viral S protein is incorporated into an adenovirus genome in vitro. These adenovirus vectors assist with entry into the host cell and utilize the host machinery to generated viral proteins that generate an antibody response.Subunit Vaccines Subunit vaccines generate immunity by administration of a virus antigen (Fig. 8-B). These naked antigens are processed by the immune system to generate an antibody response. Typically, antigens are chosen that will best generate an immune response. For SARS-CoV-2, one of the best candidate antigens for subunit vaccine development is the spike protein. A number of teams, including Novavax, AdaptVac, the University of Pittsburgh, and EpiVax, are working on developing spike protein subunit vaccines20. mRNA Vaccines In this design, mRNA coding for the SARS-CoV-2 spike protein is injected into patients, instructing the host cells to synthesize it (Fig. 8-C). Viral proteins made by host cells will be recognized as “non-self” by the immune system, which will generate both an antibody and the cytotoxic T-cell response to it. mRNA vaccines have historically had problems that prevented effective clinical use, but recent innovations have provided resolution of these problems (Table I). mRNA vaccine delivery strategies include lipid nanoparticles, polyethylene glycol (PEG) nanoparticles, polymer liposomes, nanoemulsions, polysaccharide particles, protamine liposomes, and more29. Because the speed of the design, synthesis, and purification methods are all standard at this point, 1 company developing an mRNA vaccine against SARS-CoV-2 has indicated that it could be available as an emergency measure to health-care workers as early as autumn 202030 (Table II). DNA Plasmid Vaccine After the publication of the genetic sequence of SARS-CoV-2, the development of a DNA vaccine also became possible. Using the (+)ssRNA genome of SARS-CoV-2, complementary DNA (cDNA) sequences can be generated. These cDNA sequences can be incorporated into plasmids or small extrachromosomal double-stranded DNA (dsDNA) molecules that code for antigen expression (plasmid DNA [pDNA]) (Fig. 8-D). pDNA can replicate autonomously using host machinery. Once pDNA is introduced into host cells, it can synthesize viral antigens that are recognized as non-self, prompting the host immune system to generate an antibody and the CD8+ cytotoxic T-cell response. This method of vaccine development shares advantages similar to those previously listed for mRNA vaccines (Table II). Additionally, nucleic acids are simpler structures that obviate the potential issues with protein folding, which can hinder recombinant protein-based vaccines6. Using electroporation technology, multiple studies have demonstrated that pDNA can enter animal host cells and can result in a robust immune response31-33. This technology has been shown to be safe and tolerable in humans34. Although promising, to date, there have been no DNA vaccines approved for use in humans35. Recombinant Adenovirus Vector-Based Vaccines Recombinant viral vectors have been popularized as vaccine candidates over the past few decades for their ability to express heterologous antigens and their high immunogenicity (Fig. 8-E). Adenoviruses are non-enveloped DNA viruses36. One advantage of recombinant adenovirus vector-based vaccines is that they can be made safe and highly effective through recombinant technology. The safety of recombinant adenovirus vector-based vaccines is increased by rendering the virion replication defective37. This is achieved by inserting the antigen gene(s) in the locus of the adenovirus genome responsible for viral replication, thereby disrupting its ability to propagate36. Although most vaccines are administered either intramuscularly or intradermally, adenovirus vector-based vaccines provide the possibility of mucosal administration. This is a more convenient administration route than injection. For these reasons, many different recombinant adenovirus vector-based vaccines targeting SARS-CoV-2 are currently under development. Passive Immunization Passive immunization may be achieved by administration of convalescent plasma to a naïve or recently infected individual. Convalescent plasma provides protection against pathogens within the passively immunized individual. The protective components of the convalescent plasma are eventually broken down or removed. Once this occurs, the protective effect is lost because convalescent plasma does not “educate” or activate the immune system to provide long-lasting immunization. There are risks with transfusing convalescent plasma, including thrombotic events and immunosuppression, paradoxically leaving patients who develop the latter at a higher risk of infection. Currently, there are a number of clinical trials involving convalescent plasma for the treatment of patients with COVID-1938,39. Factors Impacting Population Immunity to COVID-19 There is, and should be, a great urgency to develop a vaccine against SARS-CoV-2. Public health measures will need to continue until the development, manufacturing, distribution, and administration of a vaccine against SARS-CoV-2 to a large proportion of the population. Even with these measures, enormous morbidity and mortality will continue. The potential case fatality rate increase from our current 0.03% to between 0.25% and 3.0% of the U.S. population while the United States reaches the herd immunity threshold (Pcrit) may be difficult to accept40,41. A number of factors, including potential transient immunity, incomplete immunity, and vaccine hesitancy, could impact the efficacy of a successful COVID-19 vaccine (Table III). TABLE III - Factors Delaying and Driving the Achievement of Expedited Effective COVID-19 Vaccine and/or Immunization Factor Explanation Possible Effect on COVID-19 Vaccine and/or Immunization Delaying Transient immunity Coronaviruses are capable of reinfection47 Immunity in individuals may require repeat vaccination Some vaccinated individuals may not be fully immune Vaccine is only partially effective May require repeat vaccination or vaccination of more individuals than Pcrit Vaccine hesitancy42 Individuals refuse, selectively use, or delay use of vaccines More difficult to achieve Pcrit No precedent for expedited development Previous record for vaccine development and approval is mumps (approximately 4 years)76; experts caution the expedited development can occur only if all necessary steps “go perfect the first time”77 Vaccine takes years to develop Prior similar (SARS-CoV) efforts have failed After 17 years of SARS vaccine development, we still do not have a working vaccine Vaccine takes years to develop Driving Advanced molecular techniques now available Allow more effective synthesis of recombinant components Development accelerated Vaccines produced “at risk”78 Scaling or manufacturing occurs before efficacy testing complete Production accelerated Prior SARS-CoV research 17 years of vaccine development completed Previous work provides knowledge base to work from Competition and collaboration Over 100 teams worldwide working on vaccine Development accelerated Vaccine hesitancy (contributed to by the antivaccination movement) is especially troubling42. A recent survey by the Associated Press (AP)-NORC Center for Public Affairs Research revealed that 20% of U.S. adults would not get vaccinated and 31% were unsure if they would when a vaccine becomes available43. A Reuters survey of U.S. adults found that 14% were “not at all interested” and an additional 10% were “not very interested” in a COVID-19 vaccine44. Vaccine-hesitant behavior is an underemphasized factor that could delay our reaching Pcrit or lead to the persistence of COVID-19 hotspots. The initial, clinically approved COVID-19 vaccine offerings likely will not be the optimum solution. This was illustrated with polio and measles vaccines, both of which went through evolution in the formulations and types that were used when drawbacks or complications were discovered in the early offerings45,46. The vaccines available, which patient groups to whom they are administered and when, attitudes toward receiving them, and their delivery methods will all evolve with time. One factor potentially substantially limiting vaccine efficacy is transient immunity. Beta coronaviruses causing seasonal illness are capable of reinfecting the same individual47. This raises concern that SARS-CoV-2 may also reinfect exposed individuals. Reinfections may be due to either waning antibody titers and memory cell populations or antigenic drift. The need for repeat vaccination could also delay the establishment of Pcrit. Another possibility is partial efficacy, meaning that only some vaccinated individuals would have full immunity. Partial immunity is still advantageous; it reduces the numbers of infected individuals needing hospitalization and those requiring care on the level of an intensive care unit. The effectiveness of developed vaccines will most likely be evaluated by titers of blocking antibodies. Vaccines that have entered into Phase-2 trials have already been assayed for blocking antibodies in their Phase-1 study subjects48. The sequential administration of different vaccines has been helpful in achieving immunity. Live attenuated and inactivated polio vaccines administered sequentially have a synergistic effect49. Furthermore, for viruses with substantial antigenic drift such as influenza, sequential immunizations help to create broadly neutralizing antibody responses for conserved epitopes50. There is a complex interplay of sex and age on immune function. In general, antibody responses to vaccines are better in women51,52, while both sexes show humoral immune responses (especially to novel antigens) that are inversely related to age53. Although multiple factors affect the time for adequate immunity to develop, a general guide is 2 to 3 weeks following the final dosing54. Problems that are of particular concern in developing a vaccine to RNA viruses are the incompletely understood phenomena of immunopotentiation and eosinophilic infiltration. Immunopotentiation is the vaccine-mediated enhancement of the viral disease rather than its prevention. This has led to hospitalization and fatalities in immunized patients55. Eosinophilic infiltration has been seen with a number of vaccines, including those against SARS-CoV56,57. Another problematic phenomenon is the antibody-dependent enhancement (ADE) of infection. ADE of infection occurs when antibody-bound viruses are internalized by cells via their complement or Fc (fragment crystallizable) receptors. This has been shown to occur in human cells with SARS-CoV58. It is not anticipated that vaccine administration will have a direct musculoskeletal impact. However, the time to successful completion, testing, and distribution will have immense implications for the extent and timeliness of orthopaedic care provision59-61. It is unclear what standard methods or best practices will be followed during the production and distribution of competing viable vaccines, as many of the technologies currently being used have never resulted in doses produced at scale. We hope that multiple vaccines and their producers will be leveraged to gain more expedient and effective distribution and administration to the non-immune populace. Immunization with any candidate vaccines should not lead to increased perioperative complications. Patients should be vaccinated weeks before elective orthopaedic procedures to allow the establishment of an adequate immune response and mitigation of severe morbidity and mortality associated with perioperative COVID-1962. The great hope for the development of effective vaccines should be tempered with the reality that the requisite processes to achieve success will be arduous. There will likely be many fits and starts; we must gird ourselves to this reality. The protective measures that we have instituted, including social distancing, masks, personal protective equipment, and the increased use of testing, will be a part of our lives until then. Conclusions COVID-19 has wrought enormous morbidity and mortality. Achieving Pcrit will be pivotal in our return to a lifestyle free of social distancing. Reaching Pcrit will be greatly expedited through widespread immunization. Despite an early and robust response toward developing a COVID-19 vaccine, major hurdles remain in reaching widespread clinical use. Recombinant techniques may substantially decrease this time. A partnership between the health-care community and governmental agencies should balance the need for expedited vaccine development with responsible patient safety. Appendix Supporting material provided by the authors is posted with the online version of this article as a data supplement at jbjs.org (https://links.lww.com/JBJS/G64).