Seasonal influenza and the current COVID-19 pandemic represent looming global health challenges. Efficacious and safe vaccines remain the frontline tools for mitigating both influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced diseases. This review will discuss the existing strategies for influenza vaccines and how these strategies have informed SARS-CoV-2 vaccines. It will also discuss new vaccine platforms and potential challenges for both viruses.

As highlighted by the current coronavirus-induced disease-19 (COVID-19) pandemic, the potential to respond rapidly to generate effective vaccines against emerging viruses is of critical importance. Since its establishment in 1948, the World Health Organization (WHO) has coordinated emergency responses to global health crises and pandemics (1). Although their efforts have been critical for controlling infectious diseases such as smallpox, HIV, and Ebola, their functioning primarily relies on the collaboration of United Nation member states. Unfortunately, after the 2009 H1N1 pandemic, the WHO concluded that the global community was not ready to control future pandemics (2). This concern is likely due to many factors, including the need to share genetic sequencing data, enhance the speed of vaccine design and development, and assemble the infrastructure to scale up vaccine candidate production and worldwide distribution. During the current COVID-19 pandemic, dissemination of data from rapid sequencing and identifying isolated strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has supported the generation of clinical vaccine candidates with unprecedented speed. The ability to respond so quickly is due in part to applying the knowledge gained from previous respiratory vaccine development, including influenza and other coronaviruses such as SARS and Middle East respiratory syndrome (MERS). This review describes lessons learned and challenges discovered from seasonal and pandemic influenza vaccine strategies that should inform the continued development of vaccines against the novel SARS-CoV-2.

Influenza viruses are enveloped negative-sense RNA viruses that cause acute respiratory diseases. Although influenza viruses are classified into type A, B, and C, only type A and B viruses are recognized as major drivers of human disease (35). Type A viruses are classified by the composition of the two major viral surface glycoproteins, hemagglutinin (HA) and neuraminidase. Type B viruses are separated into two distinct lineages characterized by their antigenicity (B/Victoria and B/Yamagata). Currently, the circulating seasonal influenza viruses consist of A (H1N1), A (H3N2), and the two lineages of influenza B viruses. Although there are no known pandemic strains in circulation currently, the seasonal A (H1N1) virus is the remnant of the viral strain that caused the 2009 “swine-flu” pandemic.

The challenges of influenza vaccines

A major challenge in influenza vaccine design stems from the constant evolution of influenza viruses. The error-prone activity of influenza viruses’ RNA-dependent RNA polymerase causes mutations in the viral surface proteins, allowing for escape from immune memory recognition (4, 68). The accumulation of these point mutations is referred to as genetic or antigenic drift and is largely responsible for seasonal influenza epidemics. Antigenic drift results in the generation of unique viruses that are closely related because of these small mutations. Influenza A viruses can also undergo a process referred to as antigenic shift that can create novel pandemic strains (3, 6, 9). Antigenic shift results from combining genetic composition from two or more strains of influenza viruses, which leads to the abrupt generation of a novel strain. This occurs in type A viruses that not only infect humans, but have strains that can infect or have reservoirs in other wild and domesticated species such as birds, pigs, and horses. Although not occurring frequently, if a virus that primarily infects nonhuman hosts either reassorts with a human virus or gains the ability to infect humans, novel and potentially highly virulent strains can arise, leading to pandemics (1013). Since the notorious 1918 “Spanish flu,” there have been only three other recorded cases of novel pandemic influenza strains, including H1N1, H2N2, and H3N2 (Table I).

Table I.

Previous recorded influenza pandemics

Pandemic YearInfluenza A SubtypeNonhuman Species of OriginEstimated ROEstimated Mortality Rate (%)Total Estimated DeathsReferences
1918 H1N1 Avian 1.2–3.0 2–3 20–50 million (12, 13, 191, 192
1957–1958 H2N2 Avian 1.5 <0.2 1–4 million (11, 12, 19, 193
1968–1969 H3N2 Avian 1.3–1.6 <0.2 1–4 million (11, 12, 19, 193
2009–2010 H1N1 Swine/avian 1.1–1.8 0.02 100,000–400,000 (2, 19, 25, 194
Pandemic YearInfluenza A SubtypeNonhuman Species of OriginEstimated ROEstimated Mortality Rate (%)Total Estimated DeathsReferences
1918 H1N1 Avian 1.2–3.0 2–3 20–50 million (12, 13, 191, 192
1957–1958 H2N2 Avian 1.5 <0.2 1–4 million (11, 12, 19, 193
1968–1969 H3N2 Avian 1.3–1.6 <0.2 1–4 million (11, 12, 19, 193
2009–2010 H1N1 Swine/avian 1.1–1.8 0.02 100,000–400,000 (2, 19, 25, 194

RO, reproductive number.

Other major challenges for influenza vaccine include the low efficacy against relevant circulating viral infections and limited duration of immunity. Despite the lack of a current pandemic strain, seasonal influenza still constitutes a major healthcare burden with about 5 million severe cases and 650,000 deaths annually worldwide (14). Vaccines serve as the primary preventative measure for seasonal influenza and are recommended for all healthy individuals older than 6 mo of age (15, 16). Unfortunately, the current influenza vaccines vary yearly in efficacy between 19–60% and only provide ∼3–4 mo of protection (17, 18). This low efficacy is due in part to the high levels of antigenic drift found worldwide and the selection of candidate vaccine virus (CVV) strains based on predictions 1 y prior to the vaccine year (17, 1922). Since 1948, the WHO has defined CVV strains based on collected global influenza surveillance data. Current seasonal influenza vaccine strategies are comprised of inactivated CVVs, live-attenuated CVVs, or recombinant HA proteins from CVVs to make trivalent vaccines or quadrivalent vaccines (Table II) (16). Trivalent vaccines target both subtypes of seasonal type A influenza and select either the Victoria or Yamagata lineage of type B influenza, whereas quadrivalent vaccines include both B influenza lineages (23). As opposed to seasonal influenza vaccines, development of pandemic vaccines relies less on multivalency and more on strong surveillance and preparedness strategies.

Table II.

Current influenza vaccines in the United States for 2019–2020

NameDeveloperRecommended Age
Inactivated trivalent (IIV3) 
 Fluad Seqirus ≥65 y 
 Fluzone High-Dose Sanofi Pasteur ≥65 y 
Inactivated quadrivalent (IIV4) 
 Afluria Quadrivalent Seqirus ≥6 mo 
 Fluarix Quadrivalent GlaxoSmithKline ≥6 mo 
 Flucelvax Quadrivalent Seqirus ≥4 y 
 FluLaval Quadrivalent GlaxoSmithKline ≥6 mo 
 Fluzone Quadrivalent Sanofi Pasteur ≥6 mo 
Recombinant inactivated quadrivalent (RIV4) 
Flublock Quadrivalent Sanofi Pasteur ≥18 y 
Live-attenuated quadrivalent (LAIV4) 
 FluMist Quadrivalent AstraZeneca 2–49 y 
NameDeveloperRecommended Age
Inactivated trivalent (IIV3) 
 Fluad Seqirus ≥65 y 
 Fluzone High-Dose Sanofi Pasteur ≥65 y 
Inactivated quadrivalent (IIV4) 
 Afluria Quadrivalent Seqirus ≥6 mo 
 Fluarix Quadrivalent GlaxoSmithKline ≥6 mo 
 Flucelvax Quadrivalent Seqirus ≥4 y 
 FluLaval Quadrivalent GlaxoSmithKline ≥6 mo 
 Fluzone Quadrivalent Sanofi Pasteur ≥6 mo 
Recombinant inactivated quadrivalent (RIV4) 
Flublock Quadrivalent Sanofi Pasteur ≥18 y 
Live-attenuated quadrivalent (LAIV4) 
 FluMist Quadrivalent AstraZeneca 2–49 y 

Adapted from Ref. 16.

The threat of influenza pandemics

Influenza pandemics arise when transmissible novel viruses gain the ability to infect susceptible humans without effective therapeutics to control resulting disease or infection. Surveillance of zoonotic influenza viruses with pandemic potential is the first line of prevention against future pandemics (9). To assess pandemic potential, zoonotic influenza viruses are separated into subtypes that have caused previous pandemics and those that have the rare ability to infect humans. In the past century, only H1N1, H2N2, and H3N2 viruses have caused pandemics, making these HA proteins the first tier of targets for vaccines against future pandemics (Table I) (24). Clinical trials testing H1N1 pandemic vaccines account for over 63% of all clinical trials for vaccine application against potential pandemic influenza strains, whereas the other two tier 1 viruses make up only 2% (Fig. 1A, Supplemental Table I). Tier 2 vaccine targets are defined by HA proteins from viruses that are known to have sporadically infected humans in the past (H5N1, H7N9, and H9N2). Although tier 2 viruses are not easily transmitted to humans, they can produce a very high mortality (30–60%) in humans that are infected with these viruses (25, 26). Controversial gain-of-function studies clearly demonstrate the pandemic potential of H5N1 in which substitution of as few as 3 aa allowed for aerosol droplet spread in ferrets (27, 28). Because of the high mortality and pandemic potential from H5N1, almost 24% of all pandemic influenza clinical trials focus on H5N1 vaccines (Fig. 1A, Supplemental Table I). The majority (∼78%) of the pandemic influenza clinical trial candidates use more conventional vaccine formulations incorporating inactivated split virus, commonly used for season influenza vaccines as well as inactivated whole virus and inactivated subunit vaccines (Fig. 1B, Supplemental Table I). Although historically effective, inactivated virus vaccines rely on growing the virus in cell culture or after egg adaptation, which can be laborious compared with recombinant protein or genomic-based vaccines (29). Alternative vaccine formulations, such as genomic, recombinant subunit, or viral vector–based vaccines, can overcome this limitation and potentially improve the speed of generation of future influenza vaccines. Should a zoonotic influenza virus with pandemic potential gain the ability to infect humans, the continued development and stockpiling of successful vaccines against these viruses will promote rapid scale-up vaccination processes.

FIGURE 1.

Summary of pandemic and potentially pandemic influenza vaccine clinical trials. Of 676 clinical trials tracked by the WHO, the frequency of (A) formulations used and (B) influenza subtypes targeted. Data adapted from Ref. 163.

FIGURE 1.

Summary of pandemic and potentially pandemic influenza vaccine clinical trials. Of 676 clinical trials tracked by the WHO, the frequency of (A) formulations used and (B) influenza subtypes targeted. Data adapted from Ref. 163.

Close modal

The design of universal influenza vaccines

We should strive to accomplish the ultimate goal for both seasonal and pandemic influenza vaccines in developing effective universal vaccines that generate broadly neutralizing Abs against all influenza viruses that infect humans. Broadly neutralizing influenza Abs were initially identified in patients postinfection or repeated seasonal influenza vaccinations (24, 3060). Although vaccination to specifically elicit broadly neutralizing Abs still has not been clinically successful, clinical trials using passive vaccination through convalescent serum or treatment with broadly neutralizing Abs have shown promise against severe influenza infections (30, 52). Recent National Institutes of Health guidelines define a universal influenza vaccine as one that is 75% effective at protecting against all influenza A viruses for at least 1 y in all age groups to whom the vaccine is administered (61). Any additional protection, such as cross-protection against influenza B viruses, is considered secondary. Multiple strategies to generate universal influenza vaccines have been applied, and in general, these approaches focus on generating broadly neutralizing responses against evolutionarily conserved regions of the HA stalk (24, 25, 62). Alternative approaches using adjuvants to boost vaccine efficacy also stimulate increased generation of broadly neutralizing Abs.

The adjuvants for a successful vaccine

Adjuvants can largely be categorized as either delivery systems or immune activators and often function in both arenas (63). The addition of adjuvants to vaccines has been shown to increase vaccine duration and efficacy through a variety of mechanisms (Table III). The choice of adjuvants is critically important to ensure proper immune activation and function. The most classical adjuvant added to vaccines consists of some variation of aluminum salts. Unfortunately, in the context of antiviral vaccines, these adjuvants are not highly potent and often lead to an undesired Th2 allergy-like immune response rather than the desired Th1 antiviral immune response (64, 65). Oil-in-water emulsions, such as MF59, AS03, and AF03, have assumed more prominence than aluminum salts, showing promise in clinical trials by increasing APC activation, B cell Ab production and antiviral T cell stimulation (6672). Immune activators are molecules that specifically activate host immune responses through the sensing activity of pattern-recognition receptors (PRRs), such as TLRs or NOD-like receptors (NLRs), or consist of cytokines that can drive specific immune responses. Immune activators and Ags can also be delivered using nano- and microparticles to increase their effectiveness (7388). Microparticles can be designed molecularly to mimic viral morphology using viral membrane components to create virus-like particles or using biomaterials to deliver cargo to specific cell types (63, 73, 75, 87, 8993). These studies strongly highlight the benefit of targeted delivery of adjuvants. Previous work from our group has demonstrated that polymeric microparticles composed of acetalated dextran delivering cGMP-AMP, a potent inducer of the PRR stimulator of IFN genes (STING), resulted in a significant increase of both humoral and balanced Th1/Th2 responses to influenza HA (73). Another recent study developed a novel pulmonary surfactant (PS) biomimetic microparticle loaded with cGMP-AMP, referred to as PS-GAMP (89). Addition of PS-GAMP to a variety of monovalent and trivalent vaccines delivered intranasally led to impressive heterologous protection against both type A and B influenza challenges. These reports are paving the way for developing potential universal vaccines. Combining broadly recognized vaccine Ags with strong immune-reactive adjuvants will hopefully lead to the development of universal influenza vaccines that protect against both seasonal and pandemic influenza strains.

Table III.

FDA-approved clinical vaccine adjuvants (195)

AdjuvantCompositionMechanismVaccinesReferences
Aluminum Amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate,Alum Activation of NLRP3 inflammasome and caspase-1 in DCs induces Th2 response Anthrax, DT, DTaP (Daptacel), DTaP (Infanrix), DTaP-IPV (Kinrix), DTaP-IPV (Quadracel), DTaP–Hep B–IPV (Pediarix), DTaP-IPV/Hib (Pentacel), Hep A (Havrix), Hep A (Vaqta), Hep B (Engerix-B), Hep B (Recombivax), Hep A/Hep B (Twinrix), HIB (PedvaxHIB), HPV (Gardasil 9), Japanese encephalitis (Ixiaro), MenB (Bexsero, Trumenba), Pneumococcal (Prevnar 13), Td (Tenivac), Td (Mass Biologics), Tdap (Adacel), Tdap (Boostrix) (65, 196
AS04 MPL + aluminum salt Activates TLR4 on DCs, induction of cytokines andAg-specific T cell activation Cervarix (197
MF59 Oil-in-water emulsion composed of squalene Rapid influx of CD11b+ cells, upregulation ofinflammatory cytokines and chemokines, recruitment ofAPCs Fluad (198
AS01B Liposome (containing MPL and QS-21) Activates APCs expressing TLR4, stimulates cytokine and costimulatory molecules production, promotes Ag-specific Ab responses, and stimulates CD8+ T cells Shingrix (199, 200
CpG 1018 Cytosine phosphoguanine, synthetic DNA Activates TLR9 in DCs and B cells, induction of cytokines and Ag-specific T cell activation Heplisav-B (201
No adjuvant   ActHIB, chickenpox, live zoster (Zostavax), MMR, meningococcal (Menactra, Menveo), rotavirus, seasonal influenza (except Fluad), single Ag polio (IPOL), yellow fever (195
AdjuvantCompositionMechanismVaccinesReferences
Aluminum Amorphous aluminum hydroxyphosphate sulfate, aluminum hydroxide, aluminum phosphate,Alum Activation of NLRP3 inflammasome and caspase-1 in DCs induces Th2 response Anthrax, DT, DTaP (Daptacel), DTaP (Infanrix), DTaP-IPV (Kinrix), DTaP-IPV (Quadracel), DTaP–Hep B–IPV (Pediarix), DTaP-IPV/Hib (Pentacel), Hep A (Havrix), Hep A (Vaqta), Hep B (Engerix-B), Hep B (Recombivax), Hep A/Hep B (Twinrix), HIB (PedvaxHIB), HPV (Gardasil 9), Japanese encephalitis (Ixiaro), MenB (Bexsero, Trumenba), Pneumococcal (Prevnar 13), Td (Tenivac), Td (Mass Biologics), Tdap (Adacel), Tdap (Boostrix) (65, 196
AS04 MPL + aluminum salt Activates TLR4 on DCs, induction of cytokines andAg-specific T cell activation Cervarix (197
MF59 Oil-in-water emulsion composed of squalene Rapid influx of CD11b+ cells, upregulation ofinflammatory cytokines and chemokines, recruitment ofAPCs Fluad (198
AS01B Liposome (containing MPL and QS-21) Activates APCs expressing TLR4, stimulates cytokine and costimulatory molecules production, promotes Ag-specific Ab responses, and stimulates CD8+ T cells Shingrix (199, 200
CpG 1018 Cytosine phosphoguanine, synthetic DNA Activates TLR9 in DCs and B cells, induction of cytokines and Ag-specific T cell activation Heplisav-B (201
No adjuvant   ActHIB, chickenpox, live zoster (Zostavax), MMR, meningococcal (Menactra, Menveo), rotavirus, seasonal influenza (except Fluad), single Ag polio (IPOL), yellow fever (195

ActHIB, Haemophilus b conjugate vaccine; Alum, potassium aluminum sulfate; DC, dendritic cell; DT, diphtheria toxin; DTaP, diphtheria–tetanus–pertussis (adolescent); FDA, Food and Drug Administration; Hep A, hepatitis A; Hep B, hepatitis B; Hib, Haemophilus influenza b; HPV, human papillomavirus; IPOL, inactivated polio; menB, meningococcal group B; MMR, measles, mumps, and rubella; MPL, monophosphoryl lipid A; Td, tetanus and diphtheria; TDaP, tetanus–diphtheria–pertussis (>11 y).

The key issues to consider for future influenza vaccines

There are many challenges and potential risks in the development of seasonal, pandemic, or universal influenza vaccines. There are significant challenges to generating protective vaccine responses in elderly patients who tend to have weaker immune responses and who do not generate long-lasting immune memory (94, 95). Through the use of potent adjuvants, this limitation may be addressed and overcome. Abs that are cross-reactive to multiple strains of influenza, but not cross-protective, can also pose potential risks. One of these potential risks is Ab-dependent enhancement (ADE) (96). ADE occurs when nonneutralizing Abs bind surface viral proteins facilitating Fc-mediated uptake of the virus, leading to additional cellular tropism that could cause increased viral transmission and pathogenicity (97). For influenza, ADE has been shown to occur in pigs that were vaccinated against an H1N2 virus and then challenged with H1N1pdm09 virus (98). Future vaccine strategies generating broadly reactive Ab responses should be thoroughly tested to ensure benefit against a broad array of influenza viruses. Although exceptionally rare and the mechanism is still unclear, the 1976 swine influenza vaccine has been associated with activation of autoimmune disorders such as Guillain-Barré syndrome (99, 100). Potent adjuvants also often lead to flu-like symptoms that may dissuade people from getting vaccinated (101). However, in the context of pathogenic virus infections, the benefits of strongly protective vaccines far outweigh the risks, but safety is of paramount concern and should always be thoroughly evaluated.

In late 2019, the novel coronavirus, SARS-CoV-2, gained the ability to infect humans (102104). Early in 2020, it became clear that SARS-CoV-2 was highly transmissible through person-to-person contact and showed higher lethality in older adults (104, 105). Due in large part to the lack of widespread viral tracing and poor containment during the early months of this disease, the current SARS-CoV-2 pandemic has caused 111 million cases worldwide with nearly 2.5 million deaths at an overall mortality of ∼2% [as of February 17, 2021 (106); Table IV]. Although the medical burden caused by SARS-CoV-2 is staggering, the rapid worldwide response by scientists and healthcare workers to understand the virus and its disease pathology has also been unparalleled. This rapid response accelerated developments of critical frontline therapeutics and vaccine strategies (107113). The pace of these advancements was energized through the scientific understanding of previous coronavirus epidemics and decades of vaccine research.

Table IV.

Key clinical features of coronaviruses and influenza viruses

SARS-CoV-2SARS-CoVMERS-CoVInfluenzaReferences
Receptor target ACE2 ACE2 DPP4 α2,6-Linked sialic acid (138, 140, 202, 203
Target cell population Nasal, respiratory, corneal, intestinal epithelial cells, and alveolar macrophages Epithelial cells, macrophages, monocytes, and alveolar type II cells Nonciliated bronchial and epithelial cells Ciliated epithelial cells and alveolar cells (139, 191, 204208
Incubation period (range) 2–14 d 2–10 d 2–15 d 1–4 d (202, 205, 209, 210
R0 2.2–6.47 2.0–3.0 <1 0.9–2.1 (211215
Initial clinical presentation Fever, dry cough, myalgia, and fatigue Fever, chills/rigor, myalgia, dry cough, headache, malaise, and dyspnea Fever, cough, and shortness of breath Fever, malaise, headache, and cough (216219
Affected age Patients >65 y of age represent the majority of hospitalizations and higher rates of mortality Higher rates or mortality in patients >60 y old compared with younger patients Mainly reported in adults, with children rarely affected For influenza A, children <2 y and adults >65 y have the highest relative risk (169, 206, 220, 221
Mortality 2–3% 11% 35.67% <0.1% (106, 215, 219, 222224
SARS-CoV-2SARS-CoVMERS-CoVInfluenzaReferences
Receptor target ACE2 ACE2 DPP4 α2,6-Linked sialic acid (138, 140, 202, 203
Target cell population Nasal, respiratory, corneal, intestinal epithelial cells, and alveolar macrophages Epithelial cells, macrophages, monocytes, and alveolar type II cells Nonciliated bronchial and epithelial cells Ciliated epithelial cells and alveolar cells (139, 191, 204208
Incubation period (range) 2–14 d 2–10 d 2–15 d 1–4 d (202, 205, 209, 210
R0 2.2–6.47 2.0–3.0 <1 0.9–2.1 (211215
Initial clinical presentation Fever, dry cough, myalgia, and fatigue Fever, chills/rigor, myalgia, dry cough, headache, malaise, and dyspnea Fever, cough, and shortness of breath Fever, malaise, headache, and cough (216219
Affected age Patients >65 y of age represent the majority of hospitalizations and higher rates of mortality Higher rates or mortality in patients >60 y old compared with younger patients Mainly reported in adults, with children rarely affected For influenza A, children <2 y and adults >65 y have the highest relative risk (169, 206, 220, 221
Mortality 2–3% 11% 35.67% <0.1% (106, 215, 219, 222224

The coronaviruses and associated diseases

Coronaviruses are enveloped positive-sense ssRNA viruses that can lead to a wide-range of diseases usually associated with respiratory infections (114, 115). Although there are seven coronaviruses that are known to infect humans, the majority cause only mild respiratory disease in healthy individuals (103). However, in 2002, the initial SARS-CoV first demonstrated the pandemic potential of the coronavirus family with almost a 10% mortality rate of infection (116119). Later in 2012, MERS-CoV emerged with estimated 34.4% mortality (115, 120). As with pandemic influenza strains, zoonotic viruses that gained the ability of person-to-person transmission were identified as the cause of the SARS-CoV and MERS-CoV epidemics (103, 116). Fortunately, because of international containment efforts, these two viruses only infected a limited number of people (estimated 8096 and 2494 infected individuals, respectively, for SARS-CoV and MERS-CoV). Unfortunately, in 2019, key enhanced transmissibility of SARS-CoV-2 above previous emerging coronaviruses made containment of the virus more difficult (121, 122). These challenges include the long viral incubation period (∼14 d) of SARS-CoV-2 and the increased spread in patients prior to the onset of symptoms or in patients who remain asymptomatic (123, 124). In patients who develop symptoms, infection with SARS-CoV-2 leads to highly heterogeneous outcomes, including COVID-19. Although pathology caused by SARS-CoV-2 shares many similarities to infections with influenza and previous coronaviruses, it does vary in key clinical features (Table IV). The major clinical disease, COVID-19, is characterized by fever, cough, and shortness of breath. In severe cases, there is lower respiratory illness leading to acute respiratory distress syndrome and cardiac failure (104, 125127). Other potential symptoms of SARS-CoV-2 infection that are still not fully understood and require further study include blood coagulation and neurologic and gastrointestinal symptoms (128131). There is still critical need to continue developing therapeutics against SARS-CoV-2–induced pathology, but because of high virus transmissibility, elusive nature, and economic and physiologic burdens on infected individuals, vaccinations offer the best opportunity for overcoming the ongoing pandemic.

The design of SARS-CoV-2 vaccines

The ability to rapidly develop SARS-CoV-2 vaccines was largely predicated on the research of previous coronaviruses, influenza, and other vaccine strategies (116, 132135). One of the first key predictions that guided multiple SARS-CoV-2 vaccine developments was the selection of a stabilized viral spike (S) protein as the best vaccine Ag (135137). As seen previously with SARS-CoV and MERS-CoV, the S protein of SARS-CoV-2 is critical for viral cellular adhesion and entry (Table IV) (138140). Although vaccination against the receptor-binding domain (RBD) of the S protein is sufficient to generate protective immunity, the stabilized whole S protein or whole virion as the vaccine target generates the best protection against rechallenge in animal models (115, 132, 135, 136, 141). Previous coronavirus vaccine research also indicates that SARS-CoV-2 vaccines should strive for generating strong neutralizing B cell humoral responses and antiviral T cell memory cellular responses (132, 135, 142144). Although the Ag target is critical for protective immunity, the overall formulation dictates the generation of strong humoral and cellular immune responses.

SARS-CoV-2 vaccine formulation demonstrates a major paradigm shift in vaccine design compared with classical and pandemic influenza vaccines. Currently, there are already six SARS-CoV-2 vaccines that have been approved for use by some countries, with more that are showing promise in late-stage clinical trials (Table V, Supplemental Table II). In the United States, all of the SARS-CoV-2 vaccines that are currently used are issued under emergency use authorizations by the U.S. Food and Drug Administration. Of the currently approved vaccines internationally, only the Sinopharm inactivated whole virus vaccine (BBIBP-CorV) uses a traditional vaccine formulation (145). The other currently approved SARS-CoV-2 vaccines generate S protein–specific immunity using either nonreplicating adenovirus vectors or delivery of mRNA in lipid nanoparticles (Table V). Importantly, based on phase III clinical trials, the currently approved vaccines are strongly protective, with efficacies ranging from 62 to 95% (146155). It is important to point out that comparing the efficacies of various approved vaccines is not valid because these vaccines were tested for different clinical end points and at different times during the course of the pandemic and/or in different locales. Hence, vaccine candidates may show less efficacy if they were administered later when several viral variants have already circulated to infect test subjects or in countries such as Brazil or South Africa where variants have become prevalent. Nonetheless, the SARS-CoV-2 vaccines have generally shown good efficacy, especially in preventing hospitalization or death. This high efficacy is likely driven by the generation of good neutralizing Ab responses in combination with strong Th1 T cell responses (Refs. 146, 156160; M. Meyer, Y. Wang, D. Edwards, G. R. Smith, A. B. Rubenstein, P. Ramanathan, C. E. Mire, C. Pietzsch, X. Chen, Y. Ge, et al., manuscript posted on bioRxiv, DOI: 10.1101/2021.01.25.428136; and A. B. Vogel, I. Kanevsky, Y. Che, K. A. Swanson, A. Muik, M. Vormehr, L. M. Kranz, K. C. Walzer, S. Hein, A. Güler, et al., manuscript posted on bioRxiv, DOI: 2020.2012.2011.421008). Although preclinical mRNA-based vaccines have been shown to generate strong immunity, these vaccines are the first clinically approved uses for this vaccine platform (161). According to the Milken Institute, 20% of the 248 SARS-CoV-2 vaccine candidates tracked are based on RNA- or DNA-based formulations (Fig. 2) (162). Viral vector–based vaccines, including adenovirus vectors, make up another 20% of vaccine candidates. This is vastly different from previous pandemic influenza vaccine formulations in which gene and viral vector candidates together comprised less than 3% of all vaccine formulations (Fig. 1B) (163). Furthermore, conventional formulations using attenuated whole virus, inactivated whole virus, or isolated components from inactivated whole virus that make up over 85% of pandemic influenza vaccines strategies are found in less than 10% of all SARS-CoV-2 vaccines. As the infrastructure to large-scale manufacturing and globally distribution of these novel vaccine platforms becomes established, these strategies can be used against current and future pathogens.

FIGURE 2.

Formulation of 248 preclinical and clinical current SARS-CoV-2 vaccine candidates. Adapted from Ref. 162.

FIGURE 2.

Formulation of 248 preclinical and clinical current SARS-CoV-2 vaccine candidates. Adapted from Ref. 162.

Close modal
Table V.

Current approved and emergency use SARS-CoV-2 vaccine candidates

DeveloperVaccinePhase III EfficacyPlatformPrevious Vaccine UseAgNo. of Doses (d)Storage Temp.Clinical Trial No.References
Moderna/NIAID/ Lonza/ Catalent/ Rovi/ Medidata/ BIOQUAL mRNA 1273 94% RNA; lipid nanoparticle–encapsulated mRNA SARS/MERS S protein 2 (0, 28) −20°C NCT04283461, NCT04405076, NCT04470427, NCT04649151, NCT04677660, NCT04712110 (Refs. 151, 153, 157, 178, 225228
BioNTech/Pfizer/ Fosun Pharma/ Rentschler Biopharma BNT162 95% RNA; lipid nanoparticle–encapsulated mRNA  S protein and RBD 2 (0, 28) −60 to −80°C ChiCTR2000034825, EudraCT 2020-001038-36, EudraCT 2020-003267-26, NCT04368728, NCT04380701, NCT04523571, NCT04537949, NCT04588480, NCT04649021, NCT04713553 (Refs. 152, 155, 159, 160, 229232 A. B. Vogel, manuscript posted on bioRxi, DOI: 2020.2012.2011.421008; and U. Sahin, A. Muik, E. Derhovanessian, I. Vogler, L. M. Kranz, M. Vormehr, A. Baum, K. Pascal, J. Quandt, D. Maurus, et al., medRxiv, DOI: /10.1101/2020.07.17.20140533) 
University of Oxford, Oxford Biomedica, Vaccines Manufacturing and Innovation Centre, Pall Life Sciences, Cobra Biologics, HalixBV, Advent s.r.l., Merck KGaA, the Serum Institute, Vaccitech, Catalent, CSL, and AstraZeneca/IQVIA AZD 1222 (formerly ChAdOx1) 62% Nonreplicating viral vector MERS, Influenza, TB, Chikungunya, Zika, MenB, plague S protein 0 to −7°C CTRI/2020/08/027170, EudraCT 2020-001072-15, EudraCT 2020-001228-32, ISRCTN15638344, ISRCTN89951424, NCT04324606, NCT04400838, NCT04444674, NCT04516746, NCT04540393, NCT04568031, NCT04686773, PACTR202005681895696, PACTR202006922165132 (146, 147, 154, 156, 158, 233, 234
Gamaleya Research Institute Sputnik V 92% Nonreplicating viral vector  S protein −18°C NCT04436471, NCT04437875, NCT04530396, NCT04564716, NCT04587219, NCT04640233, NCT04642339, NCT04656613, NCT04713488, NCT04741061 (149, 235
Beijing Institute of Biological Products/Sinopharm BBIBP-CorV 79% Inactivated virus  RBD dimer 2–8°C ChiCTR2000032459, ChiCTR2000034780, NCT04510207, NCT04560881 (145, 148
Janssen Pharmaceutical Companies/Beth Israel Deaconess Medical Center/Emergent BioSolutions/Catalent/Biological E/GRAM Ad26.COV2-S (JNJ-78436725) 66% Nonreplicating viral vector Ebola, HIV, respiratory syncytial virus S protein 1–2 2–8°C EudraCT 2020-002584-63, NCT04436276, NCT04505722, NCT04509947, NCT04535453, NCT04614948, ISRCTN14722499 (236
DeveloperVaccinePhase III EfficacyPlatformPrevious Vaccine UseAgNo. of Doses (d)Storage Temp.Clinical Trial No.References
Moderna/NIAID/ Lonza/ Catalent/ Rovi/ Medidata/ BIOQUAL mRNA 1273 94% RNA; lipid nanoparticle–encapsulated mRNA SARS/MERS S protein 2 (0, 28) −20°C NCT04283461, NCT04405076, NCT04470427, NCT04649151, NCT04677660, NCT04712110 (Refs. 151, 153, 157, 178, 225228
BioNTech/Pfizer/ Fosun Pharma/ Rentschler Biopharma BNT162 95% RNA; lipid nanoparticle–encapsulated mRNA  S protein and RBD 2 (0, 28) −60 to −80°C ChiCTR2000034825, EudraCT 2020-001038-36, EudraCT 2020-003267-26, NCT04368728, NCT04380701, NCT04523571, NCT04537949, NCT04588480, NCT04649021, NCT04713553 (Refs. 152, 155, 159, 160, 229232 A. B. Vogel, manuscript posted on bioRxi, DOI: 2020.2012.2011.421008; and U. Sahin, A. Muik, E. Derhovanessian, I. Vogler, L. M. Kranz, M. Vormehr, A. Baum, K. Pascal, J. Quandt, D. Maurus, et al., medRxiv, DOI: /10.1101/2020.07.17.20140533) 
University of Oxford, Oxford Biomedica, Vaccines Manufacturing and Innovation Centre, Pall Life Sciences, Cobra Biologics, HalixBV, Advent s.r.l., Merck KGaA, the Serum Institute, Vaccitech, Catalent, CSL, and AstraZeneca/IQVIA AZD 1222 (formerly ChAdOx1) 62% Nonreplicating viral vector MERS, Influenza, TB, Chikungunya, Zika, MenB, plague S protein 0 to −7°C CTRI/2020/08/027170, EudraCT 2020-001072-15, EudraCT 2020-001228-32, ISRCTN15638344, ISRCTN89951424, NCT04324606, NCT04400838, NCT04444674, NCT04516746, NCT04540393, NCT04568031, NCT04686773, PACTR202005681895696, PACTR202006922165132 (146, 147, 154, 156, 158, 233, 234
Gamaleya Research Institute Sputnik V 92% Nonreplicating viral vector  S protein −18°C NCT04436471, NCT04437875, NCT04530396, NCT04564716, NCT04587219, NCT04640233, NCT04642339, NCT04656613, NCT04713488, NCT04741061 (149, 235
Beijing Institute of Biological Products/Sinopharm BBIBP-CorV 79% Inactivated virus  RBD dimer 2–8°C ChiCTR2000032459, ChiCTR2000034780, NCT04510207, NCT04560881 (145, 148
Janssen Pharmaceutical Companies/Beth Israel Deaconess Medical Center/Emergent BioSolutions/Catalent/Biological E/GRAM Ad26.COV2-S (JNJ-78436725) 66% Nonreplicating viral vector Ebola, HIV, respiratory syncytial virus S protein 1–2 2–8°C EudraCT 2020-002584-63, NCT04436276, NCT04505722, NCT04509947, NCT04535453, NCT04614948, ISRCTN14722499 (236

GRAM, Grand River Aseptic Manufacturing; NIAID, National Institute of Allergy and Infectious Diseases.

The challenges of SARS-CoV-2 vaccines

Despite the unprecedented success of the first wave of SARS-CoV-2 vaccines, there are still multitudes of challenges and unaddressed questions. The most immediate challenge is the manufacturing, distribution, and implementation of sufficient numbers of vaccines to achieve herd immunity. Distribution of the vaccines is made difficult because of refrigeration criteria of the mRNA vaccines. Further, only one that has been approved for emergency use requires a single dose, the others that are approved need two doses to achieve protective immunity (Table V). The ongoing development of single-dose and thermostable vaccines, along with global cooperation and coordination, should improve vaccine distribution and availability (Table V, Supplemental Table II). Next, increasing the understanding of the strength and duration of vaccine-induced immunity is required to develop vaccination schedules to maintain immunity. It is also still unclear whether the SARS-CoV-2 vaccines are effective at reducing transmission or will still allow for asymptomatic spread. Preliminary findings suggest that after vaccination with the mRNAbased SARS-CoV-2 vaccines, the viral burden in infected patients is significantly lowered (164). Further studies are needed to show whether this reduction leads to decreased transmission. Early studies also suggest that immunity generated after SARS-CoV-2 infection or vaccination should endure for over a year (157, 165167). Although current data are promising, generation of robust immune responses may be more challenging in patients from high-risk groups with COVID-19 comorbidities, including elderly and immunocompromised patients and those undergoing immunomodulation or cancer therapy (168172). Vaccine responses in elderly patients against other viruses have been shown to be impaired because of a process called immune senescence (170, 173). Immune senescence causes a variety of immune dysfunction, including the reduction in development of new T and B cells and leading to decreased vaccine-elicited adaptive immune responses. Alternatively, in patients undergoing cancer therapy or immunotherapy, vaccination may not be recommended because of reduced vaccine efficacy or increase risk of adverse side effects (171, 174). Although achievement of herd immunity in the general public can help protect these groups, continued effort in SARS-CoV-2 vaccine development should also focus on protecting these high-risk groups (144, 175179). Addition of immune modulators and adjuvants could be adapted for SARS-CoV-2 vaccines to improve protective responses in these high-risk patients (180). Importantly, early vaccination studies continue to prioritize inclusion of diverse populations, including wide ranges in age, race, and at-risk individuals (Refs. 146148, 177181, and F. Zhu, et al., manuscript posted on Research Square, DOI: 10.21203/rs.3.rs-137265/v1). Potentially, the most critical challenge to address is the ability of SARS-CoV-2 to mutate, leading to viral variants that may evade established immunity (182185). Although the RNA reverse transcriptases of coronaviruses do have relatively good proofreading capability, they are known to undergo genomic mutations and recombination, promoting selection of viruses with improved viral fitness (186189). It is likely that the SARS-CoV-2 variants will not be as prevalent as seasonal influenza variants, but it is too early to know if they will require similar seasonal vaccination strategies. Thorough surveillance for these emerging variants and generation of variant-specific vaccines should overcome this potential challenge. The latter is especially feasible because the mRNA vaccine formulations allow for a quick turnaround time for next-generation vaccines. Similar to influenza, the ultimate long-term goal is the development of universal coronavirus vaccines that protect against variants of SARS-CoV-2 and future emerging coronavirus species with pandemic potential.

Although it is exciting to witness the rapid evolution of pandemic vaccine strategies, the successes and failures of previous pandemic vaccine strategies should be considered for the continued development of effective SARS-CoV-2 vaccines as well as against future emerging pathogens. The emergence of highly pathogenic coronaviruses used to be relatively rare, but since 2004, three highly lethal and pathogenic coronaviruses have emerged. This disturbing increased frequency of pathogenic coronaviruses cannot be ignored. The major focus in pandemic influenza preparedness has centered on developing universal influenza vaccines that lead to cross-protection against all potentially pathogenic strains of influenza viruses. Finding antigenic epitopes that are conserved between divergent strains of coronaviruses may lead to the development of universal target Ags that can be used for universal coronavirus vaccines and, thereby, increase preparedness to combat future emerging coronaviruses.

In the last year, the many lessons learned and innovations made during the development of SARS-CoV-2 vaccines can be integrated into future influenza and emerging pathogen vaccination strategies. The ability to develop effective and safe vaccines quickly during an ongoing pandemic is paramount to curb the infection rate of these viruses. The accelerated timeline for SARS-CoV-2 vaccine development offers a good blueprint on how to prioritize both speed and safety for generation of future pandemic vaccines (190). Also, the continued understanding and establishment of manufacturing infrastructure for promising newly licensed vaccine platforms, including RNA-based vaccines, should improve rapid large-scale manufacturing against current and emerging pathogens. Adapting these vaccine platforms to influenza vaccines may further support improved influenza pandemic preparedness and vaccine efficacy. Increasing the diversity of clinically approved vaccine formulations is important for ensuring successful protection against current and emerging pathogens. This includes developing new biomaterials for safe and effective delivery and incorporating adjuvants to cater specific robust immunity against both seasonal and pandemic viruses. It is important to consider the highly heterogeneous nature of the human population such that not all people react similarly to vaccine strategies. This increases the need to design and use a variety of vaccine platforms, thus increasing the options of protecting a wider panorama of the world’s population. Ultimately, the goals of both influenza and coronavirus vaccines should be to elicit strong herd immunity and, if at all possible, to eradicate lethal strains of these viruses from the human population.

We acknowledge Drs. Megan Schmidt and Katherine Barnett for the insightful discussions and ideas throughout the development of this review. We especially thank Dr. June Brickey for help in thorough editing of the manuscript.

This work was supported by the National Institute of Allergy and Infection Diseases (R01 AI141333 [to J.P.Y.T.]), the National Cancer Institute (T32-CA196589 [to A.M.S.]), and the University of North Carolina at Chapel Hill (Contract Agreement 23-01 [to J.P.Y.T.]).

The online version of this article contains supplemental material.

Abbreviations used in this article

ADE

Ab-dependent enhancement

COVID-19

coronavirus-induced disease-19

CVV

candidate vaccine virus

HA

hemagglutinin

MERS-CoV

Middle East respiratory syndrome CoV

PS

pulmorary surfactant

RBD

receptor-binding domain

S

spike

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

WHO

World Health Organization

1.
World Health Organization
.
2017
.
Pandemic influenza risk management: a WHO guide to inform and harmonize national and international pandemic preparedness and response
.
Available at: https://apps.who.int/iris/handle/10665/259893. Accessed: April 30, 2020
.
2.
Fineberg
H. V.
2014
.
Pandemic preparedness and response--lessons from the H1N1 influenza of 2009.
N. Engl. J. Med.
370
:
1335
1342
.
3.
Wille
M.
,
E. C.
Holmes
.
2019
.
The ecology and evolution of influenza viruses.
Cold Spring Harb. Perspect. Med.
10
:
a038489
.
4.
Petrova
V. N.
,
C. A.
Russell
.
2018
.
The evolution of seasonal influenza viruses. [Published erratum appears in 2018 Nat. Rev. Microbiol. 16: 47–60.]
Nat. Rev. Microbiol.
16
:
60
.
5.
Webster
R. G.
,
W. J.
Bean
,
O. T.
Gorman
,
T. M.
Chambers
,
Y.
Kawaoka
.
1992
.
Evolution and ecology of influenza A viruses.
Microbiol. Rev.
56
:
152
179
.
6.
Villa
M.
,
M.
Lässig
.
2017
.
Fitness cost of reassortment in human influenza.
PLoS Pathog.
13
:
e1006685
.
7.
Nelson
M. I.
,
E. C.
Holmes
.
2007
.
The evolution of epidemic influenza.
Nat. Rev. Genet.
8
:
196
205
.
8.
Treanor
J.
2004
.
Influenza vaccine--outmaneuvering antigenic shift and drift.
N. Engl. J. Med.
350
:
218
220
.
9.
Joseph
U.
,
Y. C.
Su
,
D.
Vijaykrishna
,
G. J.
Smith
.
2017
.
The ecology and adaptive evolution of influenza A interspecies transmission.
Influenza Other Respir. Viruses
11
:
74
84
.
10.
Huang
S. S.
,
D.
Banner
,
Y.
Fang
,
D. C.
Ng
,
T.
Kanagasabai
,
D. J.
Kelvin
,
A. A.
Kelvin
.
2011
.
Comparative analyses of pandemic H1N1 and seasonal H1N1, H3N2, and influenza B infections depict distinct clinical pictures in ferrets.
PLoS One
6
:
e27512
.
11.
Horimoto
T.
,
Y.
Kawaoka
.
2005
.
Influenza: lessons from past pandemics, warnings from current incidents.
Nat. Rev. Microbiol.
3
:
591
600
.
12.
Palese
P.
2004
.
Influenza: old and new threats.
Nat. Med.
10
(
12 Suppl
)
S82
S87
.
13.
Taubenberger
J. K.
,
A. H.
Reid
,
A. E.
Krafft
,
K. E.
Bijwaard
,
T. G.
Fanning
.
1997
.
Initial genetic characterization of the 1918 “Spanish” influenza virus.
Science
275
:
1793
1796
.
14.
World Health Organization
.
2017
.
Up to 650 000 people die of respiratory diseases linked to seasonal flu each year
. .
15.
Chung
J. R.
,
M. A.
Rolfes
,
B.
Flannery
,
P.
Prasad
,
A.
O’Halloran
,
S.
Garg
,
A. M.
Fry
,
J. A.
Singleton
,
M.
Patel
,
C.
Reed
.
2020
.
Effects of influenza vaccination in the United States during the 2018-2019 influenza season.
Clin. Infect. Dis.
71
:
e368
e376
16.
2019
.
Influenza vaccine for 2019-2020.
Med. Lett. Drugs Ther.
61
:
161
166
.
17.
Centers for Disease Control and Prevention
.
2020
.
CDC Seasonal Flu Vaccine Effectiveness Studies
. .
18.
Kissling
E.
,
M.
Valenciano
,
A.
Larrauri
,
B.
Oroszi
,
J. M.
Cohen
,
B.
Nunes
,
D.
Pitigoi
,
C.
Rizzo
,
J.
Rebolledo
,
I.
Paradowska-Stankiewicz
, et al
2013
.
Low and decreasing vaccine effectiveness against influenza A(H3) in 2011/12 among vaccination target groups in Europe: results from the I-MOVE multicentre case-control study.
Eurosurveillance
18
:
20390
.
19.
Ziegler
T.
,
A.
Mamahit
,
N. J.
Cox
.
2018
.
65 years of influenza surveillance by a World Health Organization-coordinated global network.
Influenza Other Respir. Viruses
12
:
558
565
.
20.
Hampson
A.
,
I.
Barr
,
N.
Cox
,
R. O.
Donis
,
H.
Siddhivinayak
,
D.
Jernigan
,
J.
Katz
,
J.
McCauley
,
F.
Motta
,
T.
Odagiri
, et al
2017
.
Improving the selection and development of influenza vaccine viruses - Report of a WHO informal consultation on improving influenza vaccine virus selection, Hong Kong SAR, China, 18-20 November 2015.
Vaccine
35
:
1104
1109
.
21.
Belongia
E. A.
,
M. D.
Simpson
,
J. P.
King
,
M. E.
Sundaram
,
N. S.
Kelley
,
M. T.
Osterholm
,
H. Q.
McLean
.
2016
.
Variable influenza vaccine effectiveness by subtype: a systematic review and meta-analysis of test-negative design studies.
Lancet Infect. Dis.
16
:
942
951
.
22.
World Health Organization
.
2020
.
WHO recommendations on the composition of influenza virus vaccines
. .
23.
Ray
R.
,
G.
Dos Santos
,
P. O.
Buck
,
C.
Claeys
,
G.
Matias
,
B. L.
Innis
,
R.
Bekkat-Berkani
.
2017
.
A review of the value of quadrivalent influenza vaccines and their potential contribution to influenza control.
Hum. Vaccin. Immunother.
13
:
1640
1652
.
24.
Nabel
G. J.
,
A. S.
Fauci
.
2010
.
Induction of unnatural immunity: prospects for a broadly protective universal influenza vaccine.
Nat. Med.
16
:
1389
1391
.
25.
Webster
R. G.
,
E. A.
Govorkova
.
2014
.
Continuing challenges in influenza.
Ann. N. Y. Acad. Sci.
1323
:
115
139
.
26.
Wang
T. T.
,
M. K.
Parides
,
P.
Palese
.
2012
.
Seroevidence for H5N1 influenza infections in humans: meta-analysis.
Science
335
:
1463
.
27.
Herfst
S.
,
E. J.
Schrauwen
,
M.
Linster
,
S.
Chutinimitkul
,
E.
de Wit
,
V. J.
Munster
,
E. M.
Sorrell
,
T. M.
Bestebroer
,
D. F.
Burke
,
D. J.
Smith
, et al
2012
.
Airborne transmission of influenza A/H5N1 virus between ferrets.
Science
336
:
1534
1541
.
28.
Imai
M.
,
T.
Watanabe
,
M.
Hatta
,
S. C.
Das
,
M.
Ozawa
,
K.
Shinya
,
G.
Zhong
,
A.
Hanson
,
H.
Katsura
,
S.
Watanabe
, et al
2012
.
Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets.
Nature
486
:
420
428
.
29.
Centers for Disease Control and Prevention
.
2020
.
How influenza (flu) vaccines are made
. .
30.
Sano
K.
,
A.
Ainai
,
T.
Suzuki
,
H.
Hasegawa
.
2017
.
The road to a more effective influenza vaccine: up to date studies and future prospects.
Vaccine
35
:
5388
5395
.
31.
Krammer
F.
,
P.
Palese
.
2019
.
Universal influenza virus vaccines that target the conserved hemagglutinin stalk and conserved sites in the head domain.
J. Infect. Dis.
219
(
Suppl_1
):
S62
S67
.
32.
Choi
A.
,
B.
Bouzya
,
K. D.
Cortés Franco
,
D.
Stadlbauer
,
A.
Rajabhathor
,
R. N.
Rouxel
,
R.
Mainil
,
M.
Van der Wielen
,
P.
Palese
,
A.
García-Sastre
, et al
2019
.
Chimeric hemagglutinin-based influenza virus vaccines induce protective stalk-specific humoral immunity and cellular responses in mice.
Immunohorizons
3
:
133
148
.
33.
Broecker
F.
,
S. T. H.
Liu
,
N.
Suntronwong
,
W.
Sun
,
M. J.
Bailey
,
R.
Nachbagauer
,
F.
Krammer
,
P.
Palese
.
2019
.
A mosaic hemagglutinin-based influenza virus vaccine candidate protects mice from challenge with divergent H3N2 strains.
NPJ Vaccines
4
:
31
.
34.
Andrews
S. F.
,
B. S.
Graham
,
J. R.
Mascola
,
A. B.
McDermott
.
2018
.
Is it possible to develop a “universal” influenza virus vaccine? immunogenetic considerations underlying B-cell biology in the development of a pan-subtype influenza A vaccine targeting the hemagglutinin stem.
Cold Spring Harb. Perspect. Biol.
10
:
a029413
.
35.
Liu
S. T. H.
,
M. A.
Behzadi
,
W.
Sun
,
A. W.
Freyn
,
W. C.
Liu
,
F.
Broecker
,
R. A.
Albrecht
,
N. M.
Bouvier
,
V.
Simon
,
R.
Nachbagauer
, et al
2018
.
Antigenic sites in influenza H1 hemagglutinin display species-specific immunodominance.
J. Clin. Invest.
128
:
4992
4996
.
36.
Chai
N.
,
L. R.
Swem
,
S.
Park
,
G.
Nakamura
,
N.
Chiang
,
A.
Estevez
,
R.
Fong
,
L.
Kamen
,
E.
Kho
,
M.
Reichelt
, et al
2017
.
A broadly protective therapeutic antibody against influenza B virus with two mechanisms of action. [Published erratum appears in 2017 Nat. Commun. 8: 15779.]
Nat. Commun.
8
:
14234
.
37.
Kallewaard
N. L.
,
D.
Corti
,
P. J.
Collins
,
U.
Neu
,
J. M.
McAuliffe
,
E.
Benjamin
,
L.
Wachter-Rosati
,
F. J.
Palmer-Hill
,
A. Q.
Yuan
,
P. A.
Walker
, et al
2016
.
Structure and function analysis of an antibody recognizing all influenza A subtypes.
Cell
166
:
596
608
.
38.
Joyce
M. G.
,
A. K.
Wheatley
,
P. V.
Thomas
,
G. Y.
Chuang
,
C.
Soto
,
R. T.
Bailer
,
A.
Druz
,
I. S.
Georgiev
,
R. A.
Gillespie
,
M.
Kanekiyo
, et al
NISC Comparative Sequencing Program
.
2016
.
Vaccine-induced antibodies that neutralize group 1 and group 2 influenza A viruses.
Cell
166
:
609
623
.
39.
Xu
H.
,
A. G.
Schmidt
,
T.
O’Donnell
,
M. D.
Therkelsen
,
T. B.
Kepler
,
M. A.
Moody
,
B. F.
Haynes
,
H. X.
Liao
,
S. C.
Harrison
,
D. E.
Shaw
.
2015
.
Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage.
Proteins
83
:
771
780
.
40.
Wu
Y.
,
M.
Cho
,
D.
Shore
,
M.
Song
,
J.
Choi
,
T.
Jiang
,
Y. Q.
Deng
,
M.
Bourgeois
,
L.
Almli
,
H.
Yang
, et al
2015
.
A potent broad-spectrum protective human monoclonal antibody crosslinking two haemagglutinin monomers of influenza A virus.
Nat. Commun.
6
:
7708
.
41.
Lee
P. S.
,
N.
Ohshima
,
R. L.
Stanfield
,
W.
Yu
,
Y.
Iba
,
Y.
Okuno
,
Y.
Kurosawa
,
I. A.
Wilson
.
2014
.
Receptor mimicry by antibody F045-092 facilitates universal binding to the H3 subtype of influenza virus.
Nat. Commun.
5
:
3614
.
42.
Wyrzucki
A.
,
C.
Dreyfus
,
I.
Kohler
,
M.
Steck
,
I. A.
Wilson
,
L.
Hangartner
.
2014
.
Alternative recognition of the conserved stem epitope in influenza A virus hemagglutinin by a VH3-30-encoded heterosubtypic antibody.
J. Virol.
88
:
7083
7092
.
43.
Crowe
J. E.
 Jr
.
2013
.
Universal flu vaccines: primum non nocere.
Sci. Transl. Med.
5
:
200fs34
.
44.
Schmidt
A. G.
,
H.
Xu
,
A. R.
Khan
,
T.
O’Donnell
,
S.
Khurana
,
L. R.
King
,
J.
Manischewitz
,
H.
Golding
,
P.
Suphaphiphat
,
A.
Carfi
, et al
2013
.
Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody.
Proc. Natl. Acad. Sci. USA
110
:
264
269
.
45.
Yasugi
M.
,
R.
Kubota-Koketsu
,
A.
Yamashita
,
N.
Kawashita
,
A.
Du
,
T.
Sasaki
,
M.
Nishimura
,
R.
Misaki
,
M.
Kuhara
,
N.
Boonsathorn
, et al
2013
.
Human monoclonal antibodies broadly neutralizing against influenza B virus.
PLoS Pathog.
9
:
e1003150
.
46.
Hu
W.
,
A.
Chen
,
Y.
Miao
,
S.
Xia
,
Z.
Ling
,
K.
Xu
,
T.
Wang
,
Y.
Xu
,
J.
Cui
,
H.
Wu
, et al
2013
.
Fully human broadly neutralizing monoclonal antibodies against influenza A viruses generated from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient.
Virology
435
:
320
328
.
47.
Taylor
D. N.
,
J. J.
Treanor
,
E. A.
Sheldon
,
C.
Johnson
,
S.
Umlauf
,
L.
Song
,
U.
Kavita
,
G.
Liu
,
L.
Tussey
,
K.
Ozer
, et al
2012
.
Development of VAX128, a recombinant hemagglutinin (HA) influenza-flagellin fusion vaccine with improved safety and immune response.
Vaccine
30
:
5761
5769
.
48.
Ekiert
D. C.
,
A. K.
Kashyap
,
J.
Steel
,
A.
Rubrum
,
G.
Bhabha
,
R.
Khayat
,
J. H.
Lee
,
M. A.
Dillon
,
R. E.
O’Neil
,
A. M.
Faynboym
, et al
2012
.
Cross-neutralization of influenza A viruses mediated by a single antibody loop.
Nature
489
:
526
532
.
49.
De Marco
D.
,
N.
Clementi
,
N.
Mancini
,
L.
Solforosi
,
G. J.
Moreno
,
X.
Sun
,
T. M.
Tumpey
,
L. V.
Gubareva
,
V.
Mishin
,
M.
Clementi
,
R.
Burioni
.
2012
.
A non-VH1-69 heterosubtypic neutralizing human monoclonal antibody protects mice against H1N1 and H5N1 viruses.
PLoS One
7
:
e34415
.
50.
Ohshima
N.
,
Y.
Iba
,
R.
Kubota-Koketsu
,
Y.
Asano
,
Y.
Okuno
,
Y.
Kurosawa
.
2011
.
Naturally occurring antibodies in humans can neutralize a variety of influenza virus strains, including H3, H1, H2, and H5.
J. Virol.
85
:
11048
11057
.
51.
Krause
J. C.
,
T.
Tsibane
,
T. M.
Tumpey
,
C. J.
Huffman
,
C. F.
Basler
,
J. E.
Crowe
Jr
.
2011
.
A broadly neutralizing human monoclonal antibody that recognizes a conserved, novel epitope on the globular head of the influenza H1N1 virus hemagglutinin.
J. Virol.
85
:
10905
10908
.
52.
Corti
D.
,
J.
Voss
,
S. J.
Gamblin
,
G.
Codoni
,
A.
Macagno
,
D.
Jarrossay
,
S. G.
Vachieri
,
D.
Pinna
,
A.
Minola
,
F.
Vanzetta
, et al
2011
.
A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins.
Science
333
:
850
856
.
53.
Ekiert
D. C.
,
R. H.
Friesen
,
G.
Bhabha
,
T.
Kwaks
,
M.
Jongeneelen
,
W.
Yu
,
C.
Ophorst
,
F.
Cox
,
H. J.
Korse
,
B.
Brandenburg
, et al
2011
.
A highly conserved neutralizing epitope on group 2 influenza A viruses.
Science
333
:
843
850
.
54.
Whittle
J. R.
,
R.
Zhang
,
S.
Khurana
,
L. R.
King
,
J.
Manischewitz
,
H.
Golding
,
P. R.
Dormitzer
,
B. F.
Haynes
,
E. B.
Walter
,
M. A.
Moody
, et al
2011
.
Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin.
Proc. Natl. Acad. Sci. USA
108
:
14216
14221
.
55.
Wrammert
J.
,
D.
Koutsonanos
,
G. M.
Li
,
S.
Edupuganti
,
J.
Sui
,
M.
Morrissey
,
M.
McCausland
,
I.
Skountzou
,
M.
Hornig
,
W. I.
Lipkin
, et al
2011
.
Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection.
J. Exp. Med.
208
:
181
193
.
56.
Kashyap
A. K.
,
J.
Steel
,
A.
Rubrum
,
A.
Estelles
,
R.
Briante
,
N. A.
Ilyushina
,
L.
Xu
,
R. E.
Swale
,
A. M.
Faynboym
,
P. K.
Foreman
, et al
2010
.
Protection from the 2009 H1N1 pandemic influenza by an antibody from combinatorial survivor-based libraries.
PLoS Pathog.
6
:
e1000990
.
57.
Burioni
R.
,
F.
Canducci
,
N.
Mancini
,
N.
Clementi
,
M.
Sassi
,
D.
De Marco
,
R. A.
Diotti
,
D.
Saita
,
M.
Sampaolo
,
G.
Sautto
, et al
2010
.
Monoclonal antibodies isolated from human B cells neutralize a broad range of H1 subtype influenza A viruses including swine-origin Influenza virus (S-OIV).
Virology
399
:
144
152
.
58.
Kashyap
A. K.
,
J.
Steel
,
A. F.
Oner
,
M. A.
Dillon
,
R. E.
Swale
,
K. M.
Wall
,
K. J.
Perry
,
A.
Faynboym
,
M.
Ilhan
,
M.
Horowitz
, et al
2008
.
Combinatorial antibody libraries from survivors of the Turkish H5N1 avian influenza outbreak reveal virus neutralization strategies.
Proc. Natl. Acad. Sci. USA
105
:
5986
5991
.
59.
Throsby
M.
,
E.
van den Brink
,
M.
Jongeneelen
,
L. L.
Poon
,
P.
Alard
,
L.
Cornelissen
,
A.
Bakker
,
F.
Cox
,
E.
van Deventer
,
Y.
Guan
, et al
2008
.
Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells.
PLoS One
3
:
e3942
.
60.
Okuno
Y.
,
Y.
Isegawa
,
F.
Sasao
,
S.
Ueda
.
1993
.
A common neutralizing epitope conserved between the hemagglutinins of influenza A virus H1 and H2 strains.
J. Virol.
67
:
2552
2558
.
61.
Erbelding
E. J.
,
D. J.
Post
,
E. J.
Stemmy
,
P. C.
Roberts
,
A. D.
Augustine
,
S.
Ferguson
,
C. I.
Paules
,
B. S.
Graham
,
A. S.
Fauci
.
2018
.
A universal influenza vaccine: the strategic plan for the national institute of allergy and infectious diseases.
J. Infect. Dis.
218
:
347
354
.
62.
Paules
C. I.
,
S. G.
Sullivan
,
K.
Subbarao
,
A. S.
Fauci
.
2018
.
Chasing seasonal influenza - the need for a universal influenza vaccine.
N. Engl. J. Med.
378
:
7
9
63.
Apostólico
J. S.
,
V. A.
Lunardelli
,
F. C.
Coirada
,
S. B.
Boscardin
,
D. S.
Rosa
.
2016
.
Adjuvants: classification, modus operandi, and licensing.
J. Immunol. Res.
2016
:
1459394
.
64.
Kool
M.
,
T.
Soullié
,
M.
van Nimwegen
,
M. A.
Willart
,
F.
Muskens
,
S.
Jung
,
H. C.
Hoogsteden
,
H.
Hammad
,
B. N.
Lambrecht
.
2008
.
Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells.
J. Exp. Med.
205
:
869
882
.
65.
Li
H.
,
S. B.
Willingham
,
J. P.
Ting
,
F.
Re
.
2008
.
Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3.
J. Immunol.
181
:
17
21
.
66.
Tregoning
J. S.
,
R. F.
Russell
,
E.
Kinnear
.
2018
.
Adjuvanted influenza vaccines.
Hum. Vaccin. Immunother.
14
:
550
564
.
67.
Nakaya
H. I.
,
E.
Clutterbuck
,
D.
Kazmin
,
L.
Wang
,
M.
Cortese
,
S. E.
Bosinger
,
N. B.
Patel
,
D. E.
Zak
,
A.
Aderem
,
T.
Dong
, et al
2016
.
Systems biology of immunity to MF59-adjuvanted versus nonadjuvanted trivalent seasonal influenza vaccines in early childhood.
Proc. Natl. Acad. Sci. USA
113
:
1853
1858
.
68.
O’Hagan
D. T.
,
G. S.
Ott
,
G. V.
Nest
,
R.
Rappuoli
,
G. D.
Giudice
.
2013
.
The history of MF59® adjuvant: a phoenix that arose from the ashes.
Expert Rev. Vaccines
12
:
13
30
.
69.
O’Hagan
D. T.
,
G. S.
Ott
,
E.
De Gregorio
,
A.
Seubert
.
2012
.
The mechanism of action of MF59 - an innately attractive adjuvant formulation.
Vaccine
30
:
4341
4348
.
70.
Garçon
N.
,
D. W.
Vaughn
,
A. M.
Didierlaurent
.
2012
.
Development and evaluation of AS03, an adjuvant system containing α-tocopherol and squalene in an oil-in-water emulsion.
Expert Rev. Vaccines
11
:
349
366
.
71.
Seubert
A.
,
S.
Calabro
,
L.
Santini
,
B.
Galli
,
A.
Genovese
,
S.
Valentini
,
S.
Aprea
,
A.
Colaprico
,
U.
D’Oro
,
M. M.
Giuliani
, et al
2011
.
Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88.
Proc. Natl. Acad. Sci. USA
108
:
11169
11174
.
72.
O’Hagan
D. T.
2007
.
MF59 is a safe and potent vaccine adjuvant that enhances protection against influenza virus infection.
Expert Rev. Vaccines
6
:
699
710
.
73.
Junkins
R. D.
,
M. D.
Gallovic
,
B. M.
Johnson
,
M. A.
Collier
,
R.
Watkins-Schulz
,
N.
Cheng
,
C. N.
David
,
C. E.
McGee
,
G. D.
Sempowski
,
I.
Shterev
, et al
2018
.
A robust microparticle platform for a STING-targeted adjuvant that enhances both humoral and cellular immunity during vaccination.
J. Control. Release
270
:
1
13
.
74.
Chen
N.
,
M. D.
Gallovic
,
P.
Tiet
,
J. P.
Ting
,
K. M.
Ainslie
,
E. M.
Bachelder
.
2018
.
Investigation of tunable acetalated dextran microparticle platform to optimize M2e-based influenza vaccine efficacy.
J. Control. Release
289
:
114
124
.
75.
Batty
C. J.
,
P.
Tiet
,
E. M.
Bachelder
,
K. M.
Ainslie
.
2018
.
Drug delivery for cancer immunotherapy and vaccines.
Pharm. Nanotechnol.
6
:
232
244
.
76.
Sehgal
K.
,
K. M.
Dhodapkar
,
M. V.
Dhodapkar
.
2014
.
Targeting human dendritic cells in situ to improve vaccines.
Immunol. Lett.
162
(
1
,
1 Pt A
):
59
67
.
77.
Silva
J. M.
,
G.
Vandermeulen
,
V. G.
Oliveira
,
S. N.
Pinto
,
C.
Rodrigues
,
A.
Salgado
,
C. A.
Afonso
,
A. S.
Viana
,
C.
Jérôme
,
L. C.
Silva
, et al
2014
.
Development of functionalized nanoparticles for vaccine delivery to dendritic cells: a mechanistic approach.
Nanomedicine (Lond.)
9
:
2639
2656
.
78.
Owen
J. L.
,
B.
Sahay
,
M.
Mohamadzadeh
.
2013
.
New generation of oral mucosal vaccines targeting dendritic cells.
Curr. Opin. Chem. Biol.
17
:
918
924
.
79.
Thomann-Harwood
L. J.
,
P.
Kaeuper
,
N.
Rossi
,
P.
Milona
,
B.
Herrmann
,
K. C.
McCullough
.
2013
.
Nanogel vaccines targeting dendritic cells: contributions of the surface decoration and vaccine cargo on cell targeting and activation.
J. Control. Release
166
:
95
105
.
80.
Iwanaga
S.
,
N.
Saito
,
H.
Sanae
,
M.
Nakamura
.
2013
.
Facile fabrication of uniform size-controlled microparticles and potentiality for tandem drug delivery system of micro/nanoparticles.
Colloids Surf. B Biointerfaces
109
:
301
306
.
81.
Peine
K. J.
,
E. M.
Bachelder
,
Z.
Vangundy
,
T.
Papenfuss
,
D. J.
Brackman
,
M. D.
Gallovic
,
K.
Schully
,
J.
Pesce
,
A.
Keane-Myers
,
K. M.
Ainslie
.
2013
.
Efficient delivery of the toll-like receptor agonists polyinosinic:polycytidylic acid and CpG to macrophages by acetalated dextran microparticles.
Mol. Pharm.
10
:
2849
2857
.
82.
Danhier
F.
,
E.
Ansorena
,
J. M.
Silva
,
R.
Coco
,
A.
Le Breton
,
V.
Préat
.
2012
.
PLGA-based nanoparticles: an overview of biomedical applications.
J. Control. Release
161
:
505
522
.
83.
Prow
T. W.
,
J. E.
Grice
,
L. L.
Lin
,
R.
Faye
,
M.
Butler
,
W.
Becker
,
E. M.
Wurm
,
C.
Yoong
,
T. A.
Robertson
,
H. P.
Soyer
,
M. S.
Roberts
.
2011
.
Nanoparticles and microparticles for skin drug delivery.
Adv. Drug Deliv. Rev.
63
:
470
491
.
84.
Kohane
D. S.
2007
.
Microparticles and nanoparticles for drug delivery.
Biotechnol. Bioeng.
96
:
203
209
.
85.
Elamanchili
P.
,
C. M.
Lutsiak
,
S.
Hamdy
,
M.
Diwan
,
J.
Samuel
.
2007
.
“Pathogen-mimicking” nanoparticles for vaccine delivery to dendritic cells.
J. Immunother.
30
:
378
395
.
86.
Reddy
S. T.
,
M. A.
Swartz
,
J. A.
Hubbell
.
2006
.
Targeting dendritic cells with biomaterials: developing the next generation of vaccines.
Trends Immunol.
27
:
573
579
.
87.
Foged
C.
,
A.
Sundblad
,
L.
Hovgaard
.
2002
.
Targeting vaccines to dendritic cells.
Pharm. Res.
19
:
229
238
.
88.
Kreuter
J.
1996
.
Nanoparticles and microparticles for drug and vaccine delivery.
J. Anat.
189
:
503
505
.
89.
Wang
J.
,
P.
Li
,
Y.
Yu
,
Y.
Fu
,
H.
Jiang
,
M.
Lu
,
Z.
Sun
,
S.
Jiang
,
L.
Lu
,
M. X.
Wu
.
2020
.
Pulmonary surfactant-biomimetic nanoparticles potentiate heterosubtypic influenza immunity.
Science
367
:
eaau0810
.
90.
Collier
M. A.
,
R. D.
Junkins
,
M. D.
Gallovic
,
B. M.
Johnson
,
M. M.
Johnson
,
A. N.
Macintyre
,
G. D.
Sempowski
,
E. M.
Bachelder
,
J. P.
Ting
,
K. M.
Ainslie
.
2018
.
Acetalated dextran microparticles for codelivery of STING and TLR7/8 agonists.
Mol. Pharm.
15
:
4933
4946
.
91.
Ho
N. I.
,
L. G. M.
Huis In ’t Veld
,
T. K.
Raaijmakers
,
G. J.
Adema
.
2018
.
Adjuvants enhancing cross-presentation by dendritic cells: the key to more effective vaccines?
Front. Immunol.
9
:
2874
.
92.
Bachelder
E. M.
,
T. T.
Beaudette
,
K. E.
Broaders
,
J. M.
Fréchet
,
M. T.
Albrecht
,
A. J.
Mateczun
,
K. M.
Ainslie
,
J. T.
Pesce
,
A. M.
Keane-Myers
.
2010
.
In vitro analysis of acetalated dextran microparticles as a potent delivery platform for vaccine adjuvants.
Mol. Pharm.
7
:
826
835
.
93.
Copland
M. J.
,
T.
Rades
,
N. M.
Davies
,
M. A.
Baird
.
2005
.
Lipid based particulate formulations for the delivery of antigen.
Immunol. Cell Biol.
83
:
97
105
.
94.
Young
B.
,
X.
Zhao
,
A. R.
Cook
,
C. M.
Parry
,
A.
Wilder-Smith
,
M. C.
I-Cheng
.
2017
.
Do antibody responses to the influenza vaccine persist year-round in the elderly? A systematic review and meta-analysis.
Vaccine
35
:
212
221
.
95.
Song
J. Y.
,
H. J.
Cheong
,
I. S.
Hwang
,
W. S.
Choi
,
Y. M.
Jo
,
D. W.
Park
,
G. J.
Cho
,
T. G.
Hwang
,
W. J.
Kim
.
2010
.
Long-term immunogenicity of influenza vaccine among the elderly: risk factors for poor immune response and persistence.
Vaccine
28
:
3929
3935
.
96.
Halstead
S. B.
2003
.
Neutralization and antibody-dependent enhancement of dengue viruses.
Adv. Virus Res.
60
:
421
467
.
97.
Takada
A.
,
Y.
Kawaoka
.
2003
.
Antibody-dependent enhancement of viral infection: molecular mechanisms and in vivo implications.
Rev. Med. Virol.
13
:
387
398
.
98.
Khurana
S.
,
C. L.
Loving
,
J.
Manischewitz
,
L. R.
King
,
P. C.
Gauger
,
J.
Henningson
,
A. L.
Vincent
,
H.
Golding
.
2013
.
Vaccine-induced anti-HA2 antibodies promote virus fusion and enhance influenza virus respiratory disease.
Sci. Transl. Med.
5
:
200ra114
.
99.
Kwong
J. C.
,
P. P.
Vasa
,
M. A.
Campitelli
,
S.
Hawken
,
K.
Wilson
,
L. C.
Rosella
,
T. A.
Stukel
,
N. S.
Crowcroft
,
A. J.
McGeer
,
L.
Zinman
,
S. L.
Deeks
.
2013
.
Risk of Guillain-Barré syndrome after seasonal influenza vaccination and influenza health-care encounters: a self-controlled study.
Lancet Infect. Dis.
13
:
769
776
.
100.
Polakowski
L. L.
,
S. K.
Sandhu
,
D. B.
Martin
,
R.
Ball
,
T. E.
Macurdy
,
R. L.
Franks
,
J. M.
Gibbs
,
G. F.
Kropp
,
A.
Avagyan
,
J. A.
Kelman
, et al
2013
.
Chart-confirmed guillain-barre syndrome after 2009 H1N1 influenza vaccination among the Medicare population, 2009-2010.
Am. J. Epidemiol.
178
:
962
973
.
101.
Petrovsky
N.
2015
.
Comparative safety of vaccine adjuvants: a summary of current evidence and future needs.
Drug Saf.
38
:
1059
1074
.
102.
Zhu
N.
,
D.
Zhang
,
W.
Wang
,
X.
Li
,
B.
Yang
,
J.
Song
,
X.
Zhao
,
B.
Huang
,
W.
Shi
,
R.
Lu
, et al
China Novel Coronavirus Investigating and Research Team
.
2020
.
A novel coronavirus from patients with pneumonia in China, 2019.
N. Engl. J. Med.
382
:
727
733
.
103.
Chen
Y.
,
Q.
Liu
,
D.
Guo
.
2020
.
Emerging coronaviruses: genome structure, replication, and pathogenesis. [Published erratum appears in 2020 J. Med. Virol. 92: 2249.]
J. Med. Virol.
92
:
418
423
.
104.
Zhou
P.
,
X. L.
Yang
,
X. G.
Wang
,
B.
Hu
,
L.
Zhang
,
W.
Zhang
,
H. R.
Si
,
Y.
Zhu
,
B.
Li
,
C. L.
Huang
, et al
2020
.
A pneumonia outbreak associated with a new coronavirus of probable bat origin.
Nature
579
:
270
273
.
105.
Chan
J. F.
,
S.
Yuan
,
K. H.
Kok
,
K. K.
To
,
H.
Chu
,
J.
Yang
,
F.
Xing
,
J.
Liu
,
C. C.
Yip
,
R. W.
Poon
, et al
2020
.
A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster.
Lancet
395
:
514
523
.
106.
Dong
E.
,
H.
Du
,
L.
Gardner
.
2020
.
An interactive web-based dashboard to track COVID-19 in real time. [Published erratum appears in 2020 Lancet Infect Dis. 20: e215.]
Lancet Infect. Dis.
20
:
533
534
.
107.
Umakanthan
S.
,
V. K.
Chattu
,
A. V.
Ranade
,
D.
Das
,
A.
Basavarajegowda
,
M.
Bukelo
.
2021
.
A rapid review of recent advances in diagnosis, treatment and vaccination for COVID-19.
AIMS Public Health
8
:
137
153
.
108.
Neerukonda
S. N.
,
U.
Katneni
.
2020
.
A review on SARS-CoV-2 virology, pathophysiology, animal models, and anti-viral interventions.
Pathogens
9
:
426
.
109.
Sempowski
G. D.
,
K. O.
Saunders
,
P.
Acharya
,
K. J.
Wiehe
,
B. F.
Haynes
.
2020
.
Pandemic preparedness: developing vaccines and therapeutic antibodies for COVID-19.
Cell.
181
:
1458
1463
.
110.
Zhang
J.
,
H.
Zeng
,
J.
Gu
,
H.
Li
,
L.
Zheng
,
Q.
Zou
.
2020
.
Progress and prospects on vaccine development against SARS-CoV-2.
Vaccines (Basel)
8
:
153
.
111.
World Health Organization
.
2020
.
DRAFT landscape of COVID-19 candidate vaccines – October 19, 2020
. .
112.
Sheahan
T. P.
,
A. C.
Sims
,
S.
Zhou
,
R. L.
Graham
,
A. J.
Pruijssers
,
M. L.
Agostini
,
S. R.
Leist
,
A.
Schäfer
,
K. H.
Dinnon
III
,
L. J.
Stevens
, et al
2020
.
An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice.
Sci. Transl. Med.
12
:
eabb5883
.
113.
Pruijssers
A. J.
,
A. S.
George
,
A.
Schafer
,
S. R.
Leist
,
L. E.
Gralinksi
,
K. H.
Dinnon
,
B. L.
Yount
,
M. L.
Agostini
,
L. J.
Stevens
,
J. D.
Chappell
, et al
2020
.
Remdesivir potently inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice in mice.
Cell. Rep.
32
:
107940
114.
Fehr
A. R.
,
S.
Perlman
.
2015
.
Coronaviruses: an overview of their replication and pathogenesis.
Methods Mol. Biol.
1282
:
1
23
.
115.
Graham
R. L.
,
E. F.
Donaldson
,
R. S.
Baric
.
2013
.
A decade after SARS: strategies for controlling emerging coronaviruses.
Nat. Rev. Microbiol.
11
:
836
848
.
116.
de Wit
E.
,
N.
van Doremalen
,
D.
Falzarano
,
V. J.
Munster
.
2016
.
SARS and MERS: recent insights into emerging coronaviruses.
Nat. Rev. Microbiol.
14
:
523
534
.
117.
Nicholls
J. M.
,
L. L.
Poon
,
K. C.
Lee
,
W. F.
Ng
,
S. T.
Lai
,
C. Y.
Leung
,
C. M.
Chu
,
P. K.
Hui
,
K. L.
Mak
,
W.
Lim
, et al
2003
.
Lung pathology of fatal severe acute respiratory syndrome.
Lancet
361
:
1773
1778
.
118.
Ding
Y.
,
H.
Wang
,
H.
Shen
,
Z.
Li
,
J.
Geng
,
H.
Han
,
J.
Cai
,
X.
Li
,
W.
Kang
,
D.
Weng
, et al
2003
.
The clinical pathology of severe acute respiratory syndrome (SARS): a report from China.
J. Pathol.
200
:
282
289
.
119.
Peiris
J. S.
,
C. M.
Chu
,
V. C.
Cheng
,
K. S.
Chan
,
I. F.
Hung
,
L. L.
Poon
,
K. I.
Law
,
B. S.
Tang
,
T. Y.
Hon
,
C. S.
Chan
, et al
HKU/UCH SARS Study Group
.
2003
.
Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study.
Lancet
361
:
1767
1772
.
120.
Lu
L.
,
Q.
Liu
,
L.
Du
,
S.
Jiang
.
2013
.
Middle East respiratory syndrome coronavirus (MERS-CoV): challenges in identifying its source and controlling its spread.
Microbes Infect.
15
:
625
629
.
121.
Gandhi
M.
,
D. S.
Yokoe
,
D. V.
Havlir
.
2020
.
Asymptomatic transmission, the Achilles’ heel of current strategies to control Covid-19.
N. Engl. J. Med.
382
:
2158
2160
.
122.
Cheng
P. K.
,
D. A.
Wong
,
L. K.
Tong
,
S. M.
Ip
,
A. C.
Lo
,
C. S.
Lau
,
E. Y.
Yeung
,
W. W.
Lim
.
2004
.
Viral shedding patterns of coronavirus in patients with probable severe acute respiratory syndrome.
Lancet
363
:
1699
1700
.
123.
Wölfel
R.
,
V. M.
Corman
,
W.
Guggemos
,
M.
Seilmaier
,
S.
Zange
,
M. A.
Müller
,
D.
Niemeyer
,
T. C.
Jones
,
P.
Vollmar
,
C.
Rothe
, et al
2020
.
Virological assessment of hospitalized patients with COVID-2019. [Published erratum appears in 2020 Nature 588: E35.]
Nature
581
:
465
469
.
124.
To
K. K.
,
O. T.
Tsang
,
W. S.
Leung
,
A. R.
Tam
,
T. C.
Wu
,
D. C.
Lung
,
C. C.
Yip
,
J. P.
Cai
,
J. M.
Chan
,
T. S.
Chik
, et al
2020
.
Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study.
Lancet Infect. Dis.
20
:
565
574
.
125.
Wang
C.
,
P. W.
Horby
,
F. G.
Hayden
,
G. F.
Gao
.
2020
.
A novel coronavirus outbreak of global health concern.
Lancet
395
:
470
473
.
126.
Huang
C.
,
Y.
Wang
,
X.
Li
,
L.
Ren
,
J.
Zhao
,
Y.
Hu
,
L.
Zhang
,
G.
Fan
,
J.
Xu
,
X.
Gu
, et al
2020
.
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
Lancet
395
:
497
506
.
127.
Li
J.
,
X.
Gong
,
Z.
Wang
,
R.
Chen
,
T.
Li
,
D.
Zeng
,
M.
Li
.
2020
.
Clinical features of familial clustering in patients infected with 2019 novel coronavirus in Wuhan, China.
Virus Res.
286
:
198043
.
128.
Tang
N.
,
D.
Li
,
X.
Wang
,
Z.
Sun
.
2020
.
Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
J. Thromb. Haemost.
18
:
844
847
.
129.
Han
H.
,
L.
Yang
,
R.
Liu
,
F.
Liu
,
K. L.
Wu
,
J.
Li
,
X. H.
Liu
,
C. L.
Zhu
.
2020
.
Prominent changes in blood coagulation of patients with SARS-CoV-2 infection.
Clin. Chem. Lab. Med.
58
:
1116
1120
.
130.
Mao
L.
,
H.
Jin
,
M.
Wang
,
Y.
Hu
,
S.
Chen
,
Q.
He
,
J.
Chang
,
C.
Hong
,
Y.
Zhou
,
D.
Wang
, et al
2020
.
Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
JAMA Neurol.
77
:
683
690
.
131.
Cholankeril
G.
,
A.
Podboy
,
V. I.
Aivaliotis
,
B.
Tarlow
,
E. A.
Pham
,
S. P.
Spencer
,
D.
Kim
,
A.
Hsing
,
A.
Ahmed
.
2020
.
High prevalence of concurrent gastrointestinal manifestations in patients with severe acute respiratory syndrome coronavirus 2: early experience from California.
Gastroenterology
159
:
775
777
.
132.
Padron-Regalado
E.
2020
.
Vaccines for SARS-CoV-2: lessons from other coronavirus strains. [Published erratum appears in 2021 Infect Dis. Ther. 10: 631.]
Infect. Dis. Ther.
9
:
1
20
.
133.
Diamond
M. S.
,
T. C.
Pierson
.
2020
.
The challenges of vaccine development against a new virus during a pandemic.
Cell Host Microbe
27
:
699
703
.
134.
Bradley
B. T.
,
A.
Bryan
.
2019
.
Emerging respiratory infections: the infectious disease pathology of SARS, MERS, pandemic influenza, and Legionella.
Semin. Diagn. Pathol.
36
:
152
159
.
135.
Wang
N.
,
J.
Shang
,
S.
Jiang
,
L.
Du
.
2020
.
Subunit vaccines against emerging pathogenic human coronaviruses.
Front. Microbiol.
11
:
298
.
136.
Wrapp
D.
,
N.
Wang
,
K. S.
Corbett
,
J. A.
Goldsmith
,
C. L.
Hsieh
,
O.
Abiona
,
B. S.
Graham
,
J. S.
McLellan
.
2020
.
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.
Science
367
:
1260
1263
.
137.
Premkumar
L.
,
B.
Segovia-Chumbez
,
R.
Jadi
,
D. R.
Martinez
,
R.
Raut
,
A.
Markmann
,
C.
Cornaby
,
L.
Bartelt
,
S.
Weiss
,
Y.
Park
, et al
2020
.
The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients.
Sci. Immunol.
5
:
eabc8413
.
138.
Song
W.
,
M.
Gui
,
X.
Wang
,
Y.
Xiang
.
2018
.
Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2.
PLoS Pathog.
14
:
e1007236
.
139.
Raj
V. S.
,
H.
Mou
,
S. L.
Smits
,
D. H.
Dekkers
,
M. A.
Müller
,
R.
Dijkman
,
D.
Muth
,
J. A.
Demmers
,
A.
Zaki
,
R. A.
Fouchier
, et al
2013
.
Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC.
Nature
495
:
251
254
.
140.
Shang
J.
,
G.
Ye
,
K.
Shi
,
Y.
Wan
,
C.
Luo
,
H.
Aihara
,
Q.
Geng
,
A.
Auerbach
,
F.
Li
.
2020
.
Structural basis of receptor recognition by SARS-CoV-2.
Nature
581
:
221
224
.
141.
Al-Amri
S. S.
,
A. T.
Abbas
,
L. A.
Siddiq
,
A.
Alghamdi
,
M. A.
Sanki
,
M. K.
Al-Muhanna
,
R. Y.
Alhabbab
,
E. I.
Azhar
,
X.
Li
,
A. M.
Hashem
.
2017
.
Immunogenicity of candidate MERS-CoV DNA vaccines based on the spike protein.
Sci. Rep.
7
:
44875
.
142.
Zhao
J.
,
J.
Zhao
,
A. K.
Mangalam
,
R.
Channappanavar
,
C.
Fett
,
D. K.
Meyerholz
,
S.
Agnihothram
,
R. S.
Baric
,
C. S.
David
,
S.
Perlman
.
2016
.
Airway memory CD4(+) T cells mediate protective immunity against emerging respiratory coronaviruses.
Immunity
44
:
1379
1391
.
143.
Channappanavar
R.
,
J.
Zhao
,
S.
Perlman
.
2014
.
T cell-mediated immune response to respiratory coronaviruses.
Immunol. Res.
59
:
118
128
.
144.
Jeyanathan
M.
,
S.
Afkhami
,
F.
Smaill
,
M. S.
Miller
,
B. D.
Lichty
,
Z.
Xing
.
2020
.
Immunological considerations for COVID-19 vaccine strategies.
Nat. Rev. Immunol.
20
:
615
632
.
145.
Wang
H.
,
Y.
Zhang
,
B.
Huang
,
W.
Deng
,
Y.
Quan
,
W.
Wang
,
W.
Xu
,
Y.
Zhao
,
N.
Li
,
J.
Zhang
, et al
2020
.
Development of an inactivated vaccine candidate, BBIBP-CorV, with potent protection against SARS-CoV-2.
Cell
182
:
713
721.e9
.
146.
Ramasamy
M. N.
,
A. M.
Minassian
,
K. J.
Ewer
,
A. L.
Flaxman
,
P. M.
Folegatti
,
D. R.
Owens
,
M.
Voysey
,
P. K.
Aley
,
B.
Angus
,
G.
Babbage
, et al
Oxford COVID Vaccine Trial Group
.
2021
.
Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.
Lancet
396
:
1979
1993
.
147.
Voysey
M.
,
S. A. C.
Clemens
,
S. A.
Madhi
,
L. Y.
Weckx
,
P. M.
Folegatti
,
P. K.
Aley
,
B.
Angus
,
V. L.
Baillie
,
S. L.
Barnabas
,
Q. E.
Bhorat
, et al
Oxford COVID Vaccine Trial Group
.
2021
.
Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.
Lancet
397
:
99
111
.
148.
Xia
S.
,
Y.
Zhang
,
Y.
Wang
,
H.
Wang
,
Y.
Yang
,
G. F.
Gao
,
W.
Tan
,
G.
Wu
,
M.
Xu
,
Z.
Lou
, et al
2021
.
Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial.
Lancet Infect. Dis.
21
:
39
51
.
149.
Logunov
D. Y.
,
I. V.
Dolzhikova
,
D. V.
Shcheblyakov
,
A. I.
Tukhvatulin
,
O. V.
Zubkova
,
A. S.
Dzharullaeva
,
A. V.
Kovyrshina
,
N. L.
Lubenets
,
D. M.
Grousova
,
A. S.
Erokhova
, et al
Gam-COVID-Vac Vaccine Trial Group
.
2021
.
Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia.
Lancet
397
:
671
681
.
150.
Jones
I.
,
P.
Roy
.
2021
.
Sputnik V COVID-19 vaccine candidate appears safe and effective.
Lancet
397
:
642
643
.
151.
Baden
L. R.
,
H. M.
El Sahly
,
B.
Essink
,
K.
Kotloff
,
S.
Frey
,
R.
Novak
,
D.
Diemert
,
S. A.
Spector
,
N.
Rouphael
,
C. B.
Creech
, et al
COVE Study Group
.
2021
.
Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
N. Engl. J. Med.
384
:
403
416
.
152.
Chagla
Z.
2021
.
The BNT162b2 (BioNTech/Pfizer) vaccine had 95% efficacy against COVID-19 ≥7 days after the 2nd dose.
Ann. Intern. Med.
174
:
JC15
.
153.
2021
.
FDA authorizes Moderna COVID-19 vaccine.
Med. Lett. Drugs Ther.
63
:
9
10
.
154.
Knoll
M. D.
,
C.
Wonodi
.
2021
.
Oxford-AstraZeneca COVID-19 vaccine efficacy.
Lancet
397
:
72
74
.
155.
Polack
F. P.
,
S. J.
Thomas
,
N.
Kitchin
,
J.
Absalon
,
A.
Gurtman
,
S.
Lockhart
,
J. L.
Perez
,
G.
Pérez Marc
,
E. D.
Moreira
,
C.
Zerbini
, et al
C4591001 Clinical Trial Group
.
2020
.
Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
N. Engl. J. Med.
383
:
2603
2615
.
156.
Ewer
K. J.
,
J. R.
Barrett
,
S.
Belij-Rammerstorfer
,
H.
Sharpe
,
R.
Makinson
,
R.
Morter
,
A.
Flaxman
,
D.
Wright
,
D.
Bellamy
,
M.
Bittaye
, et al
Oxford COVID Vaccine Trial Group
.
2021
.
T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial.
Nat. Med.
27
:
270
278
.
157.
Widge
A. T.
,
N. G.
Rouphael
,
L. A.
Jackson
,
E. J.
Anderson
,
P. C.
Roberts
,
M.
Makhene
,
J. D.
Chappell
,
M. R.
Denison
,
L. J.
Stevens
,
A. J.
Pruijssers
, et al
mRNA-1273 Study Group
.
2021
.
Durability of responses after SARS-CoV-2 mRNA-1273 vaccination.
N. Engl. J. Med.
384
:
80
82
.
158.
Folegatti
P. M.
,
K. J.
Ewer
,
P. K.
Aley
,
B.
Angus
,
S.
Becker
,
S.
Belij-Rammerstorfer
,
D.
Bellamy
,
S.
Bibi
,
M.
Bittaye
,
E. A.
Clutterbuck
, et al
Oxford COVID Vaccine Trial Group
.
2020
.
Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. [Published errata appear in 2020 Lancet 386: 466 and 2020 Lancet 396: 1884.]
Lancet
396
:
467
478
.
159.
Sahin
U.
,
A.
Muik
,
E.
Derhovanessian
,
I.
Vogler
,
L. M.
Kranz
,
M.
Vormehr
,
A.
Baum
,
K.
Pascal
,
J.
Quandt
,
D.
Maurus
, et al
2020
.
COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. [Published erratum appears in 2021 Nature 590: E17.]
Nature
586
:
594
599
.
160.
Li
J.
,
A.
Hui
,
X.
Zhang
,
Y.
Yang
,
R.
Tang
,
H.
Ye
,
R.
Ji
,
M.
Lin
,
Z.
Zhu
,
Ö.
Türeci
, et al
2021
.
Safety and immunogenicity of the SARS-CoV-2 BNT162b1 mRNA vaccine in younger and older Chinese adults: a randomized, placebo-controlled, double-blind phase 1 study.
Nat. Med.
DOI: 10.1038/s41591-021-01330-9.
161.
Pardi
N.
,
M. J.
Hogan
,
F. W.
Porter
,
D.
Weissman
.
2018
.
mRNA vaccines - a new era in vaccinology.
Nat. Rev. Drug Discov.
17
:
261
279
.
162.
Milken Institute
.
2020
.
COVID-19 treatment and vaccine tracker
. .
163.
World Health Organization
.
2020
.
Pandemic and potentially pandemic influenza vaccines
. .
164.
Levine-Tiefenbrun
M.
,
I.
Yelin
,
R.
Katz
,
E.
Herzel
,
Z.
Golan
,
L.
Schreiber
,
T.
Wolf
,
V.
Nadler
,
A.
Ben-Tov
,
J.
Kuint
, et al
2021
.
Initial report of decreased SARS-CoV-2 viral load after inoculation with the BNT162b2 vaccine.
Nat. Med.
DOI: .
165.
Dan
J. M.
,
J.
Mateus
,
Y.
Kato
,
K. M.
Hastie
,
E. D.
Yu
,
C. E.
Faliti
,
A.
Grifoni
,
S. I.
Ramirez
,
S.
Haupt
,
A.
Frazier
, et al
2021
.
Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.
Science
371
:
eabf4063
.
166.
Wang
Z.
,
F.
Schmidt
,
Y.
Weisblum
,
F.
Muecksch
,
C. O.
Barnes
,
S.
Finkin
,
D.
Schaefer-Babajew
,
M.
Cipolla
,
C.
Gaebler
,
J. A.
Lieberman
, et al
2021
.
mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants.
Nature
592
:
616
622
.
167.
Stadlbauer
D.
,
J.
Tan
,
K.
Jiang
,
M. M.
Hernandez
,
S.
Fabre
,
F.
Amanat
,
C.
Teo
,
G. A.
Arunkumar
,
M.
McMahon
,
C.
Capuano
, et al
2021
.
Repeated cross-sectional sero-monitoring of SARS-CoV-2 in New York City.
Nature
590
:
146
150
.
168.
Robilotti
E. V.
,
N. E.
Babady
,
P. A.
Mead
,
T.
Rolling
,
R.
Perez-Johnston
,
M.
Bernardes
,
Y.
Bogler
,
M.
Caldararo
,
C. J.
Figueroa
,
M. S.
Glickman
, et al
2020
.
Determinants of COVID-19 disease severity in patients with cancer.
Nat. Med.
26
:
1218
1223
.
169.
Mueller
A. L.
,
M. S.
McNamara
,
D. A.
Sinclair
.
2020
.
Why does COVID-19 disproportionately affect older people?
Aging (Albany NY)
12
:
9959
9981
.
170.
Gustafson
C. E.
,
C.
Kim
,
C. M.
Weyand
,
J. J.
Goronzy
.
2020
.
Influence of immune aging on vaccine responses.
J. Allergy Clin. Immunol.
145
:
1309
1321
.
171.
Ariza-Heredia
E. J.
,
R. F.
Chemaly
.
2015
.
Practical review of immunizations in adult patients with cancer.
Hum. Vaccin. Immunother.
11
:
2606
2614
.
172.
Akiyama
S.
,
S.
Hamdeh
,
D.
Micic
,
A.
Sakuraba
.
2020
.
Prevalence and clinical outcomes of COVID-19 in patients with autoimmune diseases: a systematic review and meta-analysis.
Ann. Rheum. Dis.
DOI: 10.1136/annrheumdis-2020-218946.
173.
Crooke
S. N.
,
I. G.
Ovsyannikova
,
G. A.
Poland
,
R. B.
Kennedy
.
2019
.
Immunosenescence and human vaccine immune responses.
Immun. Ageing
16
:
25
.
174.
Westra
J.
,
C.
Rondaan
,
S.
van Assen
,
M.
Bijl
.
2015
.
Vaccination of patients with autoimmune inflammatory rheumatic diseases.
Nat. Rev. Rheumatol.
11
:
135
145
.
175.
Anderson
R. M.
,
C.
Vegvari
,
J.
Truscott
,
B. S.
Collyer
.
2020
.
Challenges in creating herd immunity to SARS-CoV-2 infection by mass vaccination.
Lancet
396
:
1614
1616
.
176.
Pereira
B.
,
X. N.
Xu
,
A. N.
Akbar
.
2020
.
Targeting inflammation and immunosenescence to improve vaccine responses in the elderly.
Front. Immunol.
11
:
583019
.
177.
Wu
Z.
,
Y.
Hu
,
M.
Xu
,
Z.
Chen
,
W.
Yang
,
Z.
Jiang
,
M.
Li
,
H.
Jin
,
G.
Cui
,
P.
Chen
, et al
2021
.
Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.
Lancet Infect. Dis.
DOI: 10.1016/S1473-3099(20)30987-7.
178.
Anderson
E. J.
,
N. G.
Rouphael
,
A. T.
Widge
,
L. A.
Jackson
,
P. C.
Roberts
,
M.
Makhene
,
J. D.
Chappell
,
M. R.
Denison
,
L. J.
Stevens
,
A. J.
Pruijssers
, et al
mRNA-1273 Study Group
.
2020
.
Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults.
N. Engl. J. Med.
383
:
2427
2438
.
179.
Zhu
F. C.
,
X. H.
Guan
,
Y. H.
Li
,
J. Y.
Huang
,
T.
Jiang
,
L. H.
Hou
,
J. X.
Li
,
B. F.
Yang
,
L.
Wang
,
W. J.
Wang
, et al
2020
.
Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
Lancet
396
:
479
488
.
180.
Flores
L. E.
,
W. R.
Frontera
,
M. P.
Andrasik
,
C.
Del Rio
,
A.
Mondríguez-González
,
S. A.
Price
,
E. M.
Krantz
,
S. A.
Pergam
,
J. K.
Silver
.
2021
.
Assessment of the inclusion of racial/ethnic minority, female, and older individuals in vaccine clinical trials.
JAMA Netw. Open
4
:
e2037640
.
181.
Helfand
B. K. I.
,
M.
Webb
,
S. L.
Gartaganis
,
L.
Fuller
,
C. S.
Kwon
,
S. K.
Inouye
.
2020
.
The exclusion of older persons from vaccine and treatment trials for coronavirus disease 2019-missing the target.
JAMA Intern Med.
DOI: 10.1001/jamainternmed.2020.5084.
182.
Flemming
A.
2021
.
SARS-CoV-2 variant evades antibodies whilst maintaining fitness.
Nat. Rev. Immunol.
21
:
136
.
183.
Zucman
N.
,
F.
Uhel
,
D.
Descamps
,
D.
Roux
,
J. D.
Ricard
.
2021
.
Severe reinfection with South African SARS-CoV-2 variant 501Y.V2: A case report.
Clin Infect Dis.
DOI: 10.1093/cid/ciab129.
184.
Yurkovetskiy
L.
,
X.
Wang
,
K. E.
Pascal
,
C.
Tomkins-Tinch
,
T. P.
Nyalile
,
Y.
Wang
,
A.
Baum
,
W. E.
Diehl
,
A.
Dauphin
,
C.
Carbone
, et al
2020
.
Structural and functional analysis of the D614G SARS-CoV-2 spike protein variant.
Cell
183
:
739
751.e8
.
185.
Hou
Y. J.
,
S.
Chiba
,
P.
Halfmann
,
C.
Ehre
,
M.
Kuroda
,
K. H.
Dinnon
III
,
S. R.
Leist
,
A.
Schäfer
,
N.
Nakajima
,
K.
Takahashi
, et al
2020
.
SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo.
Science
370
:
1464
1468
.
186.
Zhu
Z.
,
K.
Meng
,
G.
Meng
.
2020
.
Genomic recombination events may reveal the evolution of coronavirus and the origin of SARS-CoV-2.
Sci. Rep.
10
:
21617
.
187.
Li
X.
,
E. E.
Giorgi
,
M. H.
Marichannegowda
,
B.
Foley
,
C.
Xiao
,
X. P.
Kong
,
Y.
Chen
,
S.
Gnanakaran
,
B.
Korber
,
F.
Gao
.
2020
.
Emergence of SARS-CoV-2 through recombination and strong purifying selection.
Sci. Adv.
6
:
eabb9153
.
188.
Yi
H.
2020
.
2019 novel coronavirus is undergoing active recombination.
Clin. Infect. Dis.
71
:
884
887
.
189.
Graham
R. L.
,
R. S.
Baric
.
2010
.
Recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission.
J. Virol.
84
:
3134
3146
.
190.
Lurie
N.
,
M.
Saville
,
R.
Hatchett
,
J.
Halton
.
2020
.
Developing Covid-19 vaccines at pandemic speed.
N. Engl. J. Med.
382
:
1969
1973
.
191.
Taubenberger
J. K.
,
A. H.
Reid
,
R. M.
Lourens
,
R.
Wang
,
G.
Jin
,
T. G.
Fanning
.
2005
.
Characterization of the 1918 influenza virus polymerase genes.
Nature
437
:
889
893
.
192.
Belshe
R. B.
2005
.
The origins of pandemic influenza--lessons from the 1918 virus.
N. Engl. J. Med.
353
:
2209
2211
.
193.
Taubenberger
J. K.
,
D. M.
Morens
.
2008
.
The pathology of influenza virus infections.
Annu. Rev. Pathol.
3
:
499
522
.
194.
Smith
G. J.
,
D.
Vijaykrishna
,
J.
Bahl
,
S. J.
Lycett
,
M.
Worobey
,
O. G.
Pybus
,
S. K.
Ma
,
C. L.
Cheung
,
J.
Raghwani
,
S.
Bhatt
, et al
2009
.
Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic.
Nature
459
:
1122
1125
.
195.
Centers for Disease Control and Prevention
.
2020
.
Adjuvants and vaccines
. .
196.
Eisenbarth
S. C.
,
O. R.
Colegio
,
W.
O’Connor
,
F. S.
Sutterwala
,
R. A.
Flavell
.
2008
.
Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants.
Nature
453
:
1122
1126
.
197.
Didierlaurent
A. M.
,
S.
Morel
,
L.
Lockman
,
S. L.
Giannini
,
M.
Bisteau
,
H.
Carlsen
,
A.
Kielland
,
O.
Vosters
,
N.
Vanderheyde
,
F.
Schiavetti
, et al
2009
.
AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity.
J. Immunol.
183
:
6186
6197
.
198.
Mosca
F.
,
E.
Tritto
,
A.
Muzzi
,
E.
Monaci
,
F.
Bagnoli
,
C.
Iavarone
,
D.
O’Hagan
,
R.
Rappuoli
,
E.
De Gregorio
.
2008
.
Molecular and cellular signatures of human vaccine adjuvants.
Proc. Natl. Acad. Sci. USA
105
:
10501
10506
.
199.
Didierlaurent
A. M.
,
C.
Collignon
,
P.
Bourguignon
,
S.
Wouters
,
K.
Fierens
,
M.
Fochesato
,
N.
Dendouga
,
C.
Langlet
,
B.
Malissen
,
B. N.
Lambrecht
, et al
2014
.
Enhancement of adaptive immunity by the human vaccine adjuvant AS01 depends on activated dendritic cells.
J. Immunol.
193
:
1920
1930
.
200.
Garçon
N.
,
M.
Van Mechelen
.
2011
.
Recent clinical experience with vaccines using MPL- and QS-21-containing adjuvant systems.
Expert Rev. Vaccines
10
:
471
486
.
201.
Bode
C.
,
G.
Zhao
,
F.
Steinhagen
,
T.
Kinjo
,
D. M.
Klinman
.
2011
.
CpG DNA as a vaccine adjuvant.
Expert Rev. Vaccines
10
:
499
511
.
202.
Chan
J. F.
,
S. K.
Lau
,
K. K.
To
,
V. C.
Cheng
,
P. C.
Woo
,
K. Y.
Yuen
.
2015
.
Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease.
Clin. Microbiol. Rev.
28
:
465
522
.
203.
Leung
H. S.
,
O. T.
Li
,
R. W.
Chan
,
M. C.
Chan
,
J. M.
Nicholls
,
L. L.
Poon
.
2012
.
Entry of influenza A Virus with a α2,6-linked sialic acid binding preference requires host fibronectin.
J. Virol.
86
:
10704
10713
.
204.
Sungnak
W.
,
N.
Huang
,
C.
Bécavin
,
M.
Berg
,
R.
Queen
,
M.
Litvinukova
,
C.
Talavera-López
,
H.
Maatz
,
D.
Reichart
,
F.
Sampaziotis
, et al
HCA Lung Biological Network
.
2020
.
SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes.
Nat. Med.
26
:
681
687
.
205.
Machhi
J.
,
J.
Herskovitz
,
A. M.
Senan
,
D.
Dutta
,
B.
Nath
,
M. D.
Oleynikov
,
W. R.
Blomberg
,
D. D.
Meigs
,
M.
Hasan
,
M.
Patel
, et al
2020
.
The natural history, pathobiology, and clinical manifestations of SARS-CoV-2 infections.
J. Neuroimmune Pharmacol.
15
:
359
386
.
206.
Gu
J.
,
C.
Korteweg
.
2007
.
Pathology and pathogenesis of severe acute respiratory syndrome.
Am. J. Pathol.
170
:
1136
1147
.
207.
Qian
Z.
,
E. A.
Travanty
,
L.
Oko
,
K.
Edeen
,
A.
Berglund
,
J.
Wang
,
Y.
Ito
,
K. V.
Holmes
,
R. J.
Mason
.
2013
.
Innate immune response of human alveolar type II cells infected with severe acute respiratory syndrome-coronavirus.
Am. J. Respir. Cell Mol. Biol.
48
:
742
748
.
208.
van Riel
D.
,
E.
de Wit
.
2020
.
Next-generation vaccine platforms for COVID-19.
Nat. Mater.
19
:
810
812
.
209.
Varia
M.
,
S.
Wilson
,
S.
Sarwal
,
A.
McGeer
,
E.
Gournis
,
E.
Galanis
,
B.
Henry
;
Hospital Outbreak Investigation Team
.
2003
.
Investigation of a nosocomial outbreak of severe acute respiratory syndrome (SARS) in Toronto, Canada.
CMAJ
169
:
285
292
.
210.
Bell
D.
,
A.
Nicoll
,
K.
Fukuda
,
P.
Horby
,
A.
Monto
,
F.
Hayden
,
C.
Wylks
,
L.
Sanders
,
J.
Van Tam
;
World Health Organization Writing Group
.
2006
.
Non-pharmaceutical interventions for pandemic influenza, international measures.
Emerg. Infect. Dis.
12
:
81
87
.
211.
Tang
B.
,
X.
Wang
,
Q.
Li
,
N. L.
Bragazzi
,
S.
Tang
,
Y.
Xiao
,
J.
Wu
.
2020
.
Estimation of the transmission risk of the 2019-nCoV and its implication for public health interventions.
J. Clin. Med.
9
:
462
.
212.
Riou
J.
,
C. L.
Althaus
.
2020
.
Pattern of early human-to-human transmission of Wuhan 2019 novel coronavirus (2019-nCoV), December 2019 to January 2020. [Published erratum appears in 2020 Euro Surveill. DOI: 10.2807/1560-7917.ES.2020.25.7.20200220c.]
Eurosurveillance
25
:
2000058
.
213.
Petersen
E.
,
M.
Koopmans
,
U.
Go
,
D. H.
Hamer
,
N.
Petrosillo
,
F.
Castelli
,
M.
Storgaard
,
S.
Al Khalili
,
L.
Simonsen
.
2020
.
Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics.
Lancet Infect. Dis.
20
:
e238
e244
.
214.
Bauch
C. T.
,
T.
Oraby
.
2013
.
Assessing the pandemic potential of MERS-CoV.
Lancet
382
:
662
664
.
215.
Grech
V.
,
M.
Borg
.
2020
.
Influenza vaccination in the COVID-19 era.
Early Hum. Dev.
148
:
105116
.
216.
Wang
Y.
,
Y.
Wang
,
Y.
Chen
,
Q.
Qin
.
2020
.
Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures.
J. Med. Virol.
92
:
568
576
.
217.
Hui
D. S.
2017
.
Epidemic and emerging coronaviruses (severe acute respiratory syndrome and Middle East respiratory syndrome).
Clin. Chest Med.
38
:
71
86
.
218.
Assiri
A.
,
J. A.
Al-Tawfiq
,
A. A.
Al-Rabeeah
,
F. A.
Al-Rabiah
,
S.
Al-Hajjar
,
A.
Al-Barrak
,
H.
Flemban
,
W. N.
Al-Nassir
,
H. H.
Balkhy
,
R. F.
Al-Hakeem
, et al
2013
.
Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study.
Lancet Infect. Dis.
13
:
752
761
.
219.
World Health Organization
.
2020
.
Q&A: influenza and COVID-19 - similarities and differences
. .
220.
Chafekar
A.
,
B. C.
Fielding
.
2018
.
MERS-CoV: understanding the latest human coronavirus threat.
Viruses
10
:
93
.
221.
Worby
C. J.
,
S. S.
Chaves
,
J.
Wallinga
,
M.
Lipsitch
,
L.
Finelli
,
E.
Goldstein
.
2015
.
On the relative role of different age groups in influenza epidemics.
Epidemics
13
:
10
16
.
222.
Petrosillo
N.
,
G.
Viceconte
,
O.
Ergonul
,
G.
Ippolito
,
E.
Petersen
.
2020
.
COVID-19, SARS and MERS: are they closely related?
Clin. Microbiol. Infect.
26
:
729
734
.
223.
Palacios Cruz
M.
,
E.
Santos
,
M. A.
Velazquez Cervantes
,
M.
Leon Juarez
.
2020
.
COVID-19, a worldwide public health emergency.
Rev. Clin. Esp.
DOI: 10.1016/j.rce.2020.03.001.
224.
Nassar
M. S.
,
M. A.
Bakhrebah
,
S. A.
Meo
,
M. S.
Alsuabeyl
,
W. A.
Zaher
.
2018
.
Middle East respiratory syndrome coronavirus (MERS-CoV) infection: epidemiology, pathogenesis and clinical characteristics.
Eur. Rev. Med. Pharmacol. Sci.
22
:
4956
4961
.
225.
Jackson
L. A.
,
E. J.
Anderson
,
N. G.
Rouphael
,
P. C.
Roberts
,
M.
Makhene
,
R. N.
Coler
,
M. P.
McCullough
,
J. D.
Chappell
,
M. R.
Denison
,
L. J.
Stevens
, et al
mRNA-1273 Study Group
.
2020
.
An mRNA vaccine against SARS-CoV-2 - preliminary report.
N. Engl. J. Med.
383
:
1920
1931
.
226.
Wu
K.
,
A. P.
Werner
,
M.
Koch
,
A.
Choi
,
E.
Narayanan
,
G. B. E.
Stewart-Jones
,
T.
Colpitts
,
H.
Bennett
,
S.
Boyoglu-Barnum
,
W.
Shi
, et al
2021
.
Serum neutralizing activity elicited by mRNA-1273 vaccine - preliminary report.
N. Engl. J. Med.
DOI: 10.1056/NEJMc2102179.
227.
Livingston
E. H.
2021
.
Necessity of 2 doses of the Pfizer and Moderna COVID-19 vaccines.
JAMA.
DOI: 10.1001/jama.2021.1375.
228.
Ledford
H.
2020
.
Moderna COVID vaccine becomes second to get US authorization.
Nature.
DOI: 10.1038/d41586-020-03593-7.
229.
Mulligan
M. J.
,
K. E.
Lyke
,
N.
Kitchin
,
J.
Absalon
,
A.
Gurtman
,
S.
Lockhart
,
K.
Neuzil
,
V.
Raabe
,
R.
Bailey
,
K. A.
Swanson
, et al
2020
.
Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. [Published erratum appears in 2021 Nature 590: E26.]
Nature
586
:
589
593
.
230.
Walsh
E. E.
,
R. W.
Frenck
Jr.
,
A. R.
Falsey
,
N.
Kitchin
,
J.
Absalon
,
A.
Gurtman
,
S.
Lockhart
,
K.
Neuzil
,
M. J.
Mulligan
,
R.
Bailey
, et al
2020
.
Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates.
N. Engl. J. Med.
383
:
2439
2450
.
231.
Muik
A.
,
A.-K.
Wallisch
,
B.
Sänger
,
K. A.
Swanson
,
J.
Mühl
,
W.
Chen
,
H.
Cai
,
R.
Sarkar
,
Ö.
Türeci
,
P. R.
Dormitzer
,
U.
Sahin
.
2021
.
Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine-elicited human sera.
Science
371
:
1152
1153
.
232.
Tanne
J. H.
2020
.
Covid-19: FDA panel votes to approve Pfizer BioNTech vaccine.
BMJ
371
:
m4799
.
233.
Barrett
J. R.
,
S.
Belij-Rammerstorfer
,
C.
Dold
,
K. J.
Ewer
,
P. M.
Folegatti
,
C.
Gilbride
,
R.
Halkerston
,
J.
Hill
,
D.
Jenkin
,
L.
Stockdale
, et al
Oxford COVID Vaccine Trial Group
.
2021
.
Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses.
Nat. Med.
27
:
279
288
.
234.
Torjesen
I.
2021
.
Covid-19: AstraZeneca vaccine is approved in EU with no upper age limit.
BMJ
372
:
n295
.
235.
Logunov
D. Y.
,
I. V.
Dolzhikova
,
O. V.
Zubkova
,
A. I.
Tukhvatulin
,
D. V.
Shcheblyakov
,
A. S.
Dzharullaeva
,
D. M.
Grousova
,
A. S.
Erokhova
,
A. V.
Kovyrshina
,
A. G.
Botikov
, et al
2020
.
Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia.
Lancet
396
:
887
897
.
236.
Sadoff
J.
,
M.
Le Gars
,
G.
Shukarev
,
D.
Heerwegh
,
C.
Truyers
,
A. M.
de Groot
,
J.
Stoop
,
S.
Tete
,
W.
Van Damme
,
I.
Leroux-Roels
, et al
2021
.
Interim results of a phase 1-2a trial of Ad26.COV2.S Covid-19 vaccine.
N. Engl. J. Med.
DOI: 10.1056/NEJMoa2034201.

The authors have no financial conflicts of interest.

Supplementary data