Impact of immune enhancement on Covid-19 polyclonal hyperimmune globulin therapy and vaccine development
Identifieur interne : 000900 ( Pmc/Corpus ); précédent : 000899; suivant : 000901Impact of immune enhancement on Covid-19 polyclonal hyperimmune globulin therapy and vaccine development
Auteurs : Ruklanthi De Alwis ; Shiwei Chen ; Esther S. Gan ; Eng Eong OoiSource :
- EBioMedicine [ 2352-3964 ] ; 2020.
Abstract
The pandemic spread of a novel coronavirus – SARS coronavirus-2 (SARS-CoV-2) as a cause of acute respiratory illness, named Covid-19, is placing the healthcare systems of many countries under unprecedented stress. Global economies are also spiraling towards a recession in fear of this new life-threatening disease. Vaccines that prevent SARS-CoV-2 infection and therapeutics that reduces the risk of severe Covid-19 are thus urgently needed. A rapid method to derive antiviral treatment for Covid-19 is the use of convalescent plasma derived hyperimmune globulin. However, both hyperimmune globulin and vaccine development face a common hurdle – the risk of antibody-mediated disease enhancement. The goal of this review is to examine the body of evidence supporting the hypothesis of immune enhancement that could be pertinent to Covid-19. We also discuss how this risk could be mitigated so that both hyperimmune globulin and vaccines could be rapidly translated to overcome the current global health crisis.
Url:
DOI: 10.1016/j.ebiom.2020.102768
PubMed: NONE
PubMed Central: 7161485
Links to Exploration step
PMC:7161485Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Impact of immune enhancement on Covid-19 polyclonal hyperimmune globulin therapy and vaccine development</title><author><name sortKey="De Alwis, Ruklanthi" sort="De Alwis, Ruklanthi" uniqKey="De Alwis R" first="Ruklanthi" last="De Alwis">Ruklanthi De Alwis</name><affiliation><nlm:aff id="aff0001">Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</nlm:aff></affiliation><affiliation><nlm:aff id="aff0002">Viral Research and Experimental Medicine Centre, SingHealth Duke-NUS Academic Medical Centre, Singapore</nlm:aff></affiliation></author><author><name sortKey="Chen, Shiwei" sort="Chen, Shiwei" uniqKey="Chen S" first="Shiwei" last="Chen">Shiwei Chen</name><affiliation><nlm:aff id="aff0001">Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</nlm:aff></affiliation></author><author><name sortKey="Gan, Esther S" sort="Gan, Esther S" uniqKey="Gan E" first="Esther S." last="Gan">Esther S. Gan</name><affiliation><nlm:aff id="aff0001">Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</nlm:aff></affiliation></author><author><name sortKey="Ooi, Eng Eong" sort="Ooi, Eng Eong" uniqKey="Ooi E" first="Eng Eong" last="Ooi">Eng Eong Ooi</name><affiliation><nlm:aff id="aff0001">Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</nlm:aff></affiliation><affiliation><nlm:aff id="aff0002">Viral Research and Experimental Medicine Centre, SingHealth Duke-NUS Academic Medical Centre, Singapore</nlm:aff></affiliation><affiliation><nlm:aff id="aff0003">Saw Swee Hock School of Public Health, National University of Singapore, Singapore</nlm:aff></affiliation><affiliation><nlm:aff id="aff0004">Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmc">7161485</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161485</idno><idno type="RBID">PMC:7161485</idno><idno type="doi">10.1016/j.ebiom.2020.102768</idno><idno type="pmid">NONE</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000900</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000900</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Impact of immune enhancement on Covid-19 polyclonal hyperimmune globulin therapy and vaccine development</title><author><name sortKey="De Alwis, Ruklanthi" sort="De Alwis, Ruklanthi" uniqKey="De Alwis R" first="Ruklanthi" last="De Alwis">Ruklanthi De Alwis</name><affiliation><nlm:aff id="aff0001">Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</nlm:aff></affiliation><affiliation><nlm:aff id="aff0002">Viral Research and Experimental Medicine Centre, SingHealth Duke-NUS Academic Medical Centre, Singapore</nlm:aff></affiliation></author><author><name sortKey="Chen, Shiwei" sort="Chen, Shiwei" uniqKey="Chen S" first="Shiwei" last="Chen">Shiwei Chen</name><affiliation><nlm:aff id="aff0001">Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</nlm:aff></affiliation></author><author><name sortKey="Gan, Esther S" sort="Gan, Esther S" uniqKey="Gan E" first="Esther S." last="Gan">Esther S. Gan</name><affiliation><nlm:aff id="aff0001">Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</nlm:aff></affiliation></author><author><name sortKey="Ooi, Eng Eong" sort="Ooi, Eng Eong" uniqKey="Ooi E" first="Eng Eong" last="Ooi">Eng Eong Ooi</name><affiliation><nlm:aff id="aff0001">Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</nlm:aff></affiliation><affiliation><nlm:aff id="aff0002">Viral Research and Experimental Medicine Centre, SingHealth Duke-NUS Academic Medical Centre, Singapore</nlm:aff></affiliation><affiliation><nlm:aff id="aff0003">Saw Swee Hock School of Public Health, National University of Singapore, Singapore</nlm:aff></affiliation><affiliation><nlm:aff id="aff0004">Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore</nlm:aff></affiliation></author></analytic><series><title level="j">EBioMedicine</title><idno type="eISSN">2352-3964</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The pandemic spread of a novel coronavirus – SARS coronavirus-2 (SARS-CoV-2) as a cause of acute respiratory illness, named Covid-19, is placing the healthcare systems of many countries under unprecedented stress. Global economies are also spiraling towards a recession in fear of this new life-threatening disease. Vaccines that prevent SARS-CoV-2 infection and therapeutics that reduces the risk of severe Covid-19 are thus urgently needed. A rapid method to derive antiviral treatment for Covid-19 is the use of convalescent plasma derived hyperimmune globulin. However, both hyperimmune globulin and vaccine development face a common hurdle – the risk of antibody-mediated disease enhancement. The goal of this review is to examine the body of evidence supporting the hypothesis of immune enhancement that could be pertinent to Covid-19. We also discuss how this risk could be mitigated so that both hyperimmune globulin and vaccines could be rapidly translated to overcome the current global health crisis.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Guan, W J" uniqKey="Guan W">W.J. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">EBioMedicine</journal-id><journal-id journal-id-type="iso-abbrev">EBioMedicine</journal-id><journal-title-group><journal-title>EBioMedicine</journal-title></journal-title-group><issn pub-type="epub">2352-3964</issn><publisher><publisher-name>The Author(s). Published by Elsevier B.V.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmc">7161485</article-id><article-id pub-id-type="publisher-id">S2352-3964(20)30143-2</article-id><article-id pub-id-type="doi">10.1016/j.ebiom.2020.102768</article-id><article-id pub-id-type="publisher-id">102768</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Impact of immune enhancement on Covid-19 polyclonal hyperimmune globulin therapy and vaccine development</article-title></title-group><contrib-group><contrib contrib-type="author" id="au0001"><name><surname>de Alwis</surname><given-names>Ruklanthi</given-names></name><xref rid="aff0001" ref-type="aff">a</xref><xref rid="aff0002" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au0002"><name><surname>Chen</surname><given-names>Shiwei</given-names></name><xref rid="aff0001" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au0003"><name><surname>Gan</surname><given-names>Esther S.</given-names></name><xref rid="aff0001" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au0004"><name><surname>Ooi</surname><given-names>Eng Eong</given-names></name><email>engeong.ooi@duke-nus.edu.sg</email><xref rid="aff0001" ref-type="aff">a</xref><xref rid="aff0002" ref-type="aff">b</xref><xref rid="aff0003" ref-type="aff">c</xref><xref rid="aff0004" ref-type="aff">d</xref><xref rid="cor0001" ref-type="corresp">⁎</xref></contrib></contrib-group><aff id="aff0001"><label>a</label>Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</aff><aff id="aff0002"><label>b</label>Viral Research and Experimental Medicine Centre, SingHealth Duke-NUS Academic Medical Centre, Singapore</aff><aff id="aff0003"><label>c</label>Saw Swee Hock School of Public Health, National University of Singapore, Singapore</aff><aff id="aff0004"><label>d</label>Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore</aff><author-notes><corresp id="cor0001"><label>⁎</label>Correspondence to: Eng Eong Ooi <email>engeong.ooi@duke-nus.edu.sg</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>16</day><month>4</month><year>2020</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="epub"><day>16</day><month>4</month><year>2020</year></pub-date><elocation-id>102768</elocation-id><history><date date-type="received"><day>18</day><month>3</month><year>2020</year></date><date date-type="rev-recd"><day>5</day><month>4</month><year>2020</year></date><date date-type="accepted"><day>9</day><month>4</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 The Author(s). Published by Elsevier B.V.</copyright-statement><copyright-year>2020</copyright-year><copyright-holder></copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><abstract id="abs0001"><p>The pandemic spread of a novel coronavirus – SARS coronavirus-2 (SARS-CoV-2) as a cause of acute respiratory illness, named Covid-19, is placing the healthcare systems of many countries under unprecedented stress. Global economies are also spiraling towards a recession in fear of this new life-threatening disease. Vaccines that prevent SARS-CoV-2 infection and therapeutics that reduces the risk of severe Covid-19 are thus urgently needed. A rapid method to derive antiviral treatment for Covid-19 is the use of convalescent plasma derived hyperimmune globulin. However, both hyperimmune globulin and vaccine development face a common hurdle – the risk of antibody-mediated disease enhancement. The goal of this review is to examine the body of evidence supporting the hypothesis of immune enhancement that could be pertinent to Covid-19. We also discuss how this risk could be mitigated so that both hyperimmune globulin and vaccines could be rapidly translated to overcome the current global health crisis.</p></abstract><kwd-group id="keys0001"><title>Keywords</title><kwd>COVID-19</kwd><kwd>SARS-CoV-2</kwd><kwd>Coronavirus</kwd><kwd>Polyclonal hyperimmune globulin</kwd><kwd>Vaccines</kwd></kwd-group></article-meta></front><body><sec id="sec0001"><label>1</label><title>Introduction</title><p id="para0001">SARS coronavirus-2 (SARS-CoV-2) that emerged as an outbreak in Hubei province of China has now rapidly spread to many parts of the world causing a pandemic. Infection with SARS-CoV-2 results in a pulmonary disease, named Covid-19, which is proving to be a major global health burden <xref rid="bib0001" ref-type="bibr">[1]</xref>. Substantial proportion of cases progress to severe disease, where approximately 5% of patients require intensive care support and over 20% of critical cases succumb to the disease <xref rid="bib0002" ref-type="bibr">[2]</xref>. While overall mortality rate is likely to be lower than the current estimates, as the prevalence of mildly symptomatic cases has yet to be clearly defined, Covid-19 nonetheless represents a global health emergency. There are no licensed vaccines or proven antiviral therapy to protect or treat against Covid-19. Hence once infected, case management is entirely supportive care <xref rid="bib0002" ref-type="bibr">[2]</xref>. Antiviral therapy that effectively arrests disease progression and efficacious vaccines that protect against severe Covid-19 is thus urgently required to meet medical and public health needs.</p><p id="para0002">To meet these needs, various groups have made remarkable strides in bringing new therapeutics and vaccines into clinical development within a very short period of time. A convergence between therapeutics and vaccines for Covid-19 is the harnessing of the immune response to SARS CoV-2.</p><p id="para0003">A rapidly implementable approach to the development of antivirals is the use of plasma-derived polyclonal hyperimmune globulin. Convalescent Covid-19 patients can be expected to have reasonably high titers of neutralizing antibodies against SARS-CoV-2. Plasmapheresis could be used to collect sufficient volumes of plasma from individuals who have recovered from SARS-CoV-2 infection, pooled and fractionated to produce hyperimmune globulin for infusion into acutely ill Covid-19 patients. Alternatively, fresh frozen plasma could also be delivered without additional fractionation. Such approaches have been explored for patients with viral pneumonia, including SARS and severe influenza <xref rid="bib0003" ref-type="bibr">[3]</xref>, <xref rid="bib0004" ref-type="bibr">[4]</xref>, <xref rid="bib0005" ref-type="bibr">[5]</xref>. Results have been mostly positive although many of such therapies have not been formally evaluated through a randomized, double-blind, placebo-controlled clinical trial. Theoretically, high titers of neutralizing antibody could reduce viral dissemination from infected to uninfected cells in the respiratory tract. When given soon after illness onset, this therapy could thus not only prevent disease progression, it could also lead to more rapid viral clearance and hence patient de-isolation. The latter would enable limited isolation wards to be made available to new Covid-19 patients sooner, enabling management of a larger number of Covid-19 patients despite finite containment capacity.</p><p id="para0004">Under normal circumstances, vaccine development would take years to get from concept to clinical trials. However, lessons from research on the related SARS-CoV and MERS-CoV have enabled rapid design of SARS-CoV-2 vaccine candidates for clinical development [<xref rid="bib0006" ref-type="bibr">6</xref>,<xref rid="bib0007" ref-type="bibr">7</xref>]. These vaccines have a common goal, i.e. to elicit polyclonal antibody responses against the spike protein of SARS-CoV-2 to neutralize viral infection. The vaccine candidates encompass a large diversity of vaccine platforms including mRNA, DNA, nanoparticle, subunit, and viral vectors <xref rid="bib0008" ref-type="bibr">[8]</xref>. Some of the new technological platforms, such as DNA and mRNA vaccines, can theoretically enable millions of vaccine doses to be rapidly manufactured within months and deployed to regions of need [<xref rid="bib0009" ref-type="bibr">9</xref>,<xref rid="bib0010" ref-type="bibr">10</xref>]. Indeed, unprecedented in the modern history of infectious diseases and vaccines, a vaccine candidate entered Phase I clinical trials within three months of the discovery of SARS-CoV-2. The World Health Organization (WHO) has announced that a licensed vaccine should be available for widespread use by mid-2021.</p><p id="para0005">While development of both hyperimmune globulin therapy and vaccine against SARS-CoV-2 are promising, they both pose a common theoretical safety concern <xref rid="bib0011" ref-type="bibr">[11]</xref>. Experimental studies have suggested the possibility of immune-enhanced disease of SARS-CoV and MERS-CoV infections, which may thus similarly occur with SARS-CoV-2 infection (as discussed below). The goal of this mini review is thus to examine the evidence for such concerns to guide decision making on therapeutics and vaccines for Covid-19.</p><p id="para0006">Immune enhancement of disease can theoretically occur in two ways. Firstly, non-neutralizing or sub-neutralizing levels of antibodies can enhance SARS-CoV-2 infection into target cells. Secondly, antibodies could enhance inflammation and hence severity of pulmonary disease. An overview of these antibody dependent infection and immunopathology enhancement effects are summarized in <xref rid="fig0001" ref-type="fig">Figure 1</xref>. Each of these possibilities would be discussed in turn below.<fig id="fig0001"><label>Figure 1</label><caption><p>Mechanism of ADE and antibody mediated immunopathology. <italic>Left panel</italic>: For ADE, immune complex internalization is mediated by the engagement of activating Fc receptors on the cell surface. Co-ligation of inhibitory receptors then results in the inhibition of antiviral responses which leads to increased viral replication. <italic>Right panel</italic>: Antibodies can cause immunopathology by activating the complement pathway or antibody-dependent cellular cytotoxicity (ADCC). For both pathways, excessive immune activation results in the release of cytokines and chemokines, leading to enhanced disease pathology.</p></caption><alt-text id="alt0001">Figure 1</alt-text><graphic xlink:href="gr1_lrg"></graphic></fig></p></sec><sec id="sec0002"><label>2</label><title>ADE of SARS-CoV-2 infection</title><sec id="sec0003"><label>2.1</label><title>Background</title><p id="para0007">The concern with antibody-dependent enhancement (ADE) of CoV infection arose from observations with feline infectious peritonitis virus (FIPV). FIPV infects myeloid-derived cells, such as macrophages, in cats <xref rid="bib0012" ref-type="bibr">[12]</xref>. As the target cell of FIPV also expresses fragment crystallizable (Fc) receptors, antibody decorated FIPV could activate Fc receptors for entry into macrophages. Indeed, vaccines that produce low titers of neutralizing antibodies elicited more severe peritonitis and higher mortality rates in vaccinated kittens <xref rid="bib0013" ref-type="bibr">[13]</xref>. Concerns were also raised on the possibility of ADE for SARS-CoV and MERS-CoV infections <xref rid="bib0014" ref-type="bibr">[14]</xref>.</p></sec><sec id="sec0004"><label>2.2</label><title>The Science</title><p id="para0008">ADE of infection can be elicited <italic>in vitro</italic> for many different viruses, including human immunodeficiency virus [<xref rid="bib0015" ref-type="bibr">15</xref>,<xref rid="bib0016" ref-type="bibr">16</xref>], influenza <xref rid="bib0017" ref-type="bibr">[17]</xref> and Ebola viruses [<xref rid="bib0018" ref-type="bibr">18</xref>,<xref rid="bib0019" ref-type="bibr">19</xref>]. Similarly, <italic>in vitro</italic> ADE of wild-type virus and pseudotype viruses into Fc receptor-expressing myeloid-derived cells in the presence of sub-neutralizing concentrations of immune sera has also been described for both SARS-CoV and MERS-CoV [<xref rid="bib0014" ref-type="bibr">14</xref>,<xref rid="bib0020" ref-type="bibr">[20]</xref>, <xref rid="bib0021" ref-type="bibr">[21]</xref>, <xref rid="bib0022" ref-type="bibr">[22]</xref>]. For CoVs, it has been shown that antibodies can bind the surface spike protein exposing the virus to proteolytic activation and Fc receptor-mediated entry <xref rid="bib0020" ref-type="bibr">[20]</xref>. However, <italic>in vitro</italic> observations need to be interpreted with caution, since few diseases have been clinically associated with ADE. The most prominent disease associated with ADE is arguably dengue, where infection with one serotype of dengue virus (DENV) predisposes a person to a more severe disease upon secondary infection with a heterologous DENV serotype [<xref rid="bib0023" ref-type="bibr">23</xref>,<xref rid="bib0024" ref-type="bibr">24</xref>]. A similar phenomenon was responsible for increased hospitalization rates following vaccination of dengue-naïve individuals with the chimeric tetravalent yellow fever-dengue vaccine, Dengvaxia® <xref rid="bib0025" ref-type="bibr">[25]</xref>. Besides dengue, several other viruses have shown clinical or epidemiological evidence to support the notion of ADE. Two notable examples of vaccine-induced ADE are respiratory syncytial virus (RSV) <xref rid="bib0026" ref-type="bibr">[26]</xref>, <xref rid="bib0027" ref-type="bibr">[27]</xref>, <xref rid="bib0028" ref-type="bibr">[28]</xref>, <xref rid="bib0029" ref-type="bibr">[29]</xref> and atypical measles [<xref rid="bib0030" ref-type="bibr">30</xref>,<xref rid="bib0031" ref-type="bibr">31</xref>], where severe disease was more prevalent following vaccination with inactivated virions. Unlike the above-mentioned viral diseases, there is neither clinical nor epidemiological evidence in humans to suggest ADE of CoV infection in severe disease. Re-infection with human CoVs has been observed and there is no report that sequential infection is more severe than primary infection. Likewise, there is also no evidence to suggest that the severity of SARS or MERS is linked to baseline cross-reactive CoV antibodies <xref rid="bib0032" ref-type="bibr">[32]</xref>.</p><p id="para0009">ADE starts when antibody-bound virus binds activating Fc receptors to initiate Fc receptor-mediated endocytosis or phagocytosis. This process facilitates virus entry into Fc receptor-expressing monocytes, macrophages and dendritic cells. However, binding to activating Fc receptors alone is insufficient for ADE. This is because activating Fc receptors trigger signaling molecules that also induce interferon (IFN) stimulated gene (ISG) expression, independent of type-I IFN <xref rid="bib0033" ref-type="bibr">[33]</xref>. ISGs have potent antiviral activities. Consequently, for ADE to occur, viruses must evolve ways to repress such antiviral responses in target cells. For instance, ADE of DENV infection is also dependent on binding of DENV to a co-receptor, the leukocyte immunoglobulin-like receptor B1 (LILRB1) <xref rid="bib0034" ref-type="bibr">[34]</xref>. Signaling from LILRB1 inhibits the pathway that induces ISG expression to create an intracellular environment favorable for viral replication <xref rid="bib0034" ref-type="bibr">[34]</xref>, <xref rid="bib0035" ref-type="bibr">[35]</xref>, <xref rid="bib0036" ref-type="bibr">[36]</xref>. Moreover, we have recently reported that DENV has, in addition to binding LILRB1, also evolved other ways to fundamentally alter the host cell response during antibody-mediated infection, to favor viral replication <xref rid="bib0037" ref-type="bibr">[37]</xref>. Consequently, viruses that exploit ADE must (1) target Fc receptor-expressing cells for infection and (2) have evolved mechanisms to overcome the activating Fc receptor triggered antiviral and other responses in myeloid-derived cells <xref rid="bib0023" ref-type="bibr">[23]</xref>. For viruses to evolve such abilities, Fc receptor-expressing cells must be their primary target so that positive selection can take place. However, currently SARS-CoV-2 has thus far been found to infect angiotensin converting enzyme 2 (ACE2)-expressing epithelial cells <xref rid="bib0038" ref-type="bibr">[38]</xref>. Further studies will be needed to determine the potential of SARS-CoV-2 in infecting myeloid-derived cells <xref rid="bib0039" ref-type="bibr">[39]</xref> and, if any, the role of ADE of SARS-CoV-2 infection in the clinical pathogenesis of Covid-19.</p></sec></sec><sec id="sec0005"><label>3</label><title>Antibody-enhanced immunopathology</title><sec id="sec0006"><label>3.1</label><title>Background</title><p id="para0010">Clinical support for antibody-mediated immunopathology comes from the observation that severe SARS disease manifested in week 3 of illness, at a time when respiratory tract viral load was declining due to rising antibody titers <xref rid="bib0040" ref-type="bibr">[40]</xref>. Moreover, Ho and colleagues observed that SARS patients who develop neutralizing antibody responses in the 2<sup>nd</sup> week of illness were more likely to develop severe disease compared to those who develop antibodies in the 3<sup>rd</sup> week of illness, or later <xref rid="bib0032" ref-type="bibr">[32]</xref>. A more direct link between antibodies and disease was established in Chinese rhesus macaques, when SARS-CoV-specific antibodies following vaccination or natural infection induced severe pulmonary pathology compared to untreated animals upon viral challenge <xref rid="bib0041" ref-type="bibr">[41]</xref>.</p></sec><sec id="sec0007"><label>3.2</label><title>The Science</title><p id="para0011">The exact mechanism of antibody-enhanced immunopathology in CoV infection models is not well understood. However, vaccines against viruses such as RSV displayed similar enhanced immunopathology post-vaccination. Antibody-mediated effector pathways have been postulated to be the cause of the enhanced immunopathology <xref rid="bib0042" ref-type="bibr">[42]</xref>. Besides binding to antigen and activating Fc receptor-mediated endocytosis or phagocytosis, antibodies also elicit a number of Fc-mediated responses, namely complement activation and antibody-dependent cellular cytotoxicity (ADCC). Such Fc-mediated effector pathways are generally meant to protect the host by clearing infected cells and recruiting immune cells to sites of infection [<xref rid="bib0043" ref-type="bibr">43</xref>,<xref rid="bib0044" ref-type="bibr">44</xref>]. However, an aberrant, over-stimulated Fc-mediated effector response can also lead to severe immunopathology and damage [<xref rid="bib0042" ref-type="bibr">42</xref>,<xref rid="bib0043" ref-type="bibr">43</xref>]. For example, a study observed that anti-Spike protein IgG antibody from severe SARS patients and from rhesus macaques immunized with a modified Ankara vaccinia vectored SARS CoV vaccine led to the production of proinflammatory cytokines and recruitment of inflammatory macrophages in the lung parenchyma <xref rid="bib0041" ref-type="bibr">[41]</xref>. The exact mechanism of this immune recruitment is, however, unclear. Hence, a direct link between immunopathology and antibody-dependent complement activation or ADCC during CoV infections has not yet been established.</p><p id="para0012">Despite the temporal relationship between the timings of severe SARS and antibody development [<xref rid="bib0032" ref-type="bibr">32</xref>,<xref rid="bib0040" ref-type="bibr">40</xref>], other possible explanations for the observed pathology have not been systematically excluded. Earlier antibody development could be driven by priming effect from previous human CoV infections with no impact on pathogenesis despite the temporal coincidence with severe disease. Moreover, the kinetics of antibody response is also known to be influenced by viral load <xref rid="bib0045" ref-type="bibr">[45]</xref> and innate immune responses <xref rid="bib0046" ref-type="bibr">[46]</xref>. Higher viral load and elevated cytokine/chemokine expression could thus be the main factors underpinning SARS pathology while an earlier development of neutralizing antibody could be a bystander outcome of those factors.</p><p id="para0013">Pulmonary immunopathology observed in SARS-CoV infection could also be explained by an overwhelming cascade of pro-inflammatory responses triggered by infection-induced cell death. Indeed, infection is known to exacerbate a number of cellular responses, such as the reactive oxygen species (ROS) response arising from cell stress and infection-induced metabolic perturbations, which could drive inflammation <xref rid="bib0047" ref-type="bibr">[47]</xref>. Moreover, cell death would also release purines and pyrimidines, all of which are also known to regulate cellular and immune responses, including inflammation [<xref rid="bib0048" ref-type="bibr">48</xref>,<xref rid="bib0049" ref-type="bibr">49</xref>]. Consequently, temporal association between disease worsening and lowering levels of viral load cannot be completely attributed to antibody-mediated immunopathology.</p><p id="para0014">Finally, a basis to support antibody-mediated disease enhancement is increased activation and recruitment of myeloid-derived cells to the lungs of patients. Indeed, this was the observation in vaccinated macaques, where antibody-mediated pulmonary infiltration by macrophages led to respiratory distress <xref rid="bib0041" ref-type="bibr">[41]</xref>. Histopathological findings from Covid-19 patients, however, show mainly lymphocytic rather than monocytic infiltrates in the lungs of patients who succumbed to acute respiratory distress syndrome <xref rid="bib0050" ref-type="bibr">[50]</xref>. Similarly, serendipitous pathological findings of lung cancer patients who underwent lobectomy at the time when they had undiagnosed Covid-19 did not show significant monocyte or macrophage infiltrates in the alveolar space <xref rid="bib0051" ref-type="bibr">[51]</xref>.</p></sec></sec><sec id="sec0008"><label>4</label><title>Mitigating risks</title><p id="para0015">Notwithstanding the lack of compelling clinical or histopathological evidence from human Covid-19 cases to support either ADE or antibody-enhanced immunopathology, clinical development of both vaccines and plasma therapy would meet with fewer regulatory hurdles if these risks could be mitigated right at the outset.</p><sec id="sec0009"><label>4.1</label><title>CoV vaccines</title><p id="para0016">Currently, there are multiple SARS-CoV and MERS-CoV vaccine candidates in pre-clinical or early phase clinical trials [<xref rid="bib0006" ref-type="bibr">6</xref>,<xref rid="bib0007" ref-type="bibr">7</xref>]. Animal studies on these CoVs have shown that the spike (S) protein-based vaccines (specifically the receptor binding domain, RBD) are highly immunogenic and protective against wild-type CoV challenge <xref rid="bib0052" ref-type="bibr">[52]</xref>. Vaccines that target other parts of the virus, such as the nucleocapsid, without the S protein, have shown no protection against CoV infection and increased lung pathology <xref rid="bib0053" ref-type="bibr">[53]</xref>. However, immunization with some S protein based CoV vaccines have also displayed signs of enhanced lung pathology following challenge <xref rid="bib0054" ref-type="bibr">[54]</xref>, <xref rid="bib0055" ref-type="bibr">[55]</xref>, <xref rid="bib0056" ref-type="bibr">[56]</xref>. Hence, besides the choice of antigen target, vaccine efficacy and risk of immunopathology may be dependent on other ancillary factors, including adjuvant formulation <xref rid="bib0055" ref-type="bibr">[55]</xref>, <xref rid="bib0056" ref-type="bibr">[56]</xref>, <xref rid="bib0057" ref-type="bibr">[57]</xref>, <xref rid="bib0058" ref-type="bibr">[58]</xref>, <xref rid="bib0059" ref-type="bibr">[59]</xref>, age at vaccination (older mice tend to respond poorly to vaccination) [<xref rid="bib0053" ref-type="bibr">53</xref>,<xref rid="bib0060" ref-type="bibr">60</xref>], and route of immunization <xref rid="bib0061" ref-type="bibr">[61]</xref>. <xref rid="tbl0001" ref-type="table">Table 1</xref>summarizes key findings from previous non-clinical studies on various CoV vaccine constructs. Findings from these studies could serve to guide regulatory consideration in accelerating vaccine candidates through clinical development.<table-wrap position="float" id="tbl0001"><label>Table 1</label><caption><p>Summary of published animal studies reporting protective and immunopathology phenotypes following immunization with various SARS-CoV and MERS vaccines.</p></caption><alt-text id="alt0002">Table 1</alt-text><table frame="hsides" rules="groups"><thead><tr><th valign="top">Virus</th><th valign="top">Animal</th><th valign="top">Vaccine type</th><th valign="top">Vaccination</th><th valign="top">Protective<xref rid="tb1fn1" ref-type="table-fn">a</xref></th><th valign="top">Immuno-pathology<xref rid="tb1fn2" ref-type="table-fn">b</xref></th><th valign="top">Ref.</th></tr></thead><tbody><tr><td valign="top">MERS-CoV</td><td valign="top">Mice</td><td valign="top"><xref rid="tb1fn3" ref-type="table-fn">c</xref>WIV</td><td valign="top">No Adjuvant</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0057" ref-type="bibr">[57]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Alum</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0057" ref-type="bibr">[57]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">MF59</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0057" ref-type="bibr">[57]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top">Adenovirus Vector</td><td valign="top">S1</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0063" ref-type="bibr">[63]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">S1 + CD40L</td><td valign="top">Yes</td><td valign="top">No</td><td valign="top"><xref rid="bib0063" ref-type="bibr">[63]</xref></td></tr><tr><td valign="top">SARS-CoV</td><td valign="top">Mice</td><td valign="top"><xref rid="tb1fn3" ref-type="table-fn">c</xref>WIV</td><td valign="top">No Adjuvant</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top">[<xref rid="bib0055" ref-type="bibr">55</xref>,<xref rid="bib0058" ref-type="bibr">58</xref>,<xref rid="bib0056" ref-type="bibr">56</xref>]</td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Alum</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top">[<xref rid="bib0055" ref-type="bibr">55</xref>,<xref rid="bib0058" ref-type="bibr">58</xref>,<xref rid="bib0053" ref-type="bibr">[53]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">TLR agonist</td><td valign="top">Yes</td><td valign="top"><xref rid="tb1fn4" ref-type="table-fn">d</xref>Mild</td><td valign="top"><xref rid="bib0058" ref-type="bibr">[58]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">delta inulin adjuvant</td><td valign="top">Yes</td><td valign="top">No</td><td valign="top"><xref rid="bib0056" ref-type="bibr">[56]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">No Adjuvant – Aged Mice</td><td valign="top">Partial</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0053" ref-type="bibr">[53]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Alum – Aged Mice</td><td valign="top">Partial</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0053" ref-type="bibr">[53]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"><xref rid="tb1fn5" ref-type="table-fn">e</xref>VEE Vector</td><td valign="top">S protein</td><td valign="top"></td><td valign="top"></td><td valign="top"></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Young mice</td><td valign="top">Yes</td><td valign="top">No</td><td valign="top"><xref rid="bib0060" ref-type="bibr">[60]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Aged mice</td><td valign="top">Partial</td><td valign="top">No</td><td valign="top"><xref rid="bib0060" ref-type="bibr">[60]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">N protein</td><td valign="top"></td><td valign="top"></td><td valign="top"></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Young mice</td><td valign="top">No</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0060" ref-type="bibr">[60]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Aged mice</td><td valign="top">No</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0060" ref-type="bibr">[60]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">S+N Protein</td><td valign="top"></td><td valign="top"></td><td valign="top"></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Young mice</td><td valign="top">Yes</td><td valign="top"><xref rid="tb1fn4" ref-type="table-fn">d</xref>Mild</td><td valign="top"><xref rid="bib0060" ref-type="bibr">[60]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Old mice</td><td valign="top">No</td><td valign="top"><xref rid="tb1fn4" ref-type="table-fn">d</xref>Mild</td><td valign="top"><xref rid="bib0060" ref-type="bibr">[60]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"><xref rid="tb1fn6" ref-type="table-fn">f</xref>VV Vector</td><td valign="top">S Protein</td><td valign="top">Yes</td><td valign="top">No</td><td valign="top"><xref rid="bib0076" ref-type="bibr">[76]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">N Protein</td><td valign="top">No</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0076" ref-type="bibr">[76]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">S + N Protein</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0076" ref-type="bibr">[76]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"><xref rid="tb1fn7" ref-type="table-fn">g</xref>VLP</td><td valign="top">No Adjuvant</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top">[<xref rid="bib0055" ref-type="bibr">55</xref>,<xref rid="bib0077" ref-type="bibr">77</xref>]</td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Alum</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0055" ref-type="bibr">[55]</xref><xref rid="bib0077" ref-type="bibr">[77]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top">Subunit</td><td valign="top">S Protein</td><td valign="top"></td><td valign="top"></td><td valign="top"></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">No Adjuvant</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top">[<xref rid="bib0055" ref-type="bibr">55</xref>,<xref rid="bib0056" ref-type="bibr">56</xref>]</td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Alum</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top">[<xref rid="bib0055" ref-type="bibr">55</xref>,<xref rid="bib0056" ref-type="bibr">56</xref>]</td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">delta inulin adjuvant</td><td valign="top">Yes</td><td valign="top">No</td><td valign="top"><xref rid="bib0056" ref-type="bibr">[56]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">TLR agonist</td><td valign="top">Yes</td><td valign="top">No</td><td valign="top"><xref rid="bib0059" ref-type="bibr">[59]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">S1 RBD</td><td valign="top"></td><td valign="top"></td><td valign="top"></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"><xref rid="tb1fn8" ref-type="table-fn">h</xref>FCA Adjuvant</td><td valign="top">Yes</td><td valign="top">No</td><td valign="top"><xref rid="bib0052" ref-type="bibr">[52]</xref></td></tr><tr><td valign="top"></td><td valign="top">Ferret</td><td valign="top"><xref rid="tb1fn3" ref-type="table-fn">c</xref>WIV</td><td valign="top">No adjuvant</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0078" ref-type="bibr">[78]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Alum</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0078" ref-type="bibr">[78]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"><xref rid="tb1fn9" ref-type="table-fn">i</xref>Ad Vector</td><td valign="top">S + N protein</td><td valign="top"></td><td valign="top"></td><td valign="top"></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Intra-nasal</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0078" ref-type="bibr">[78]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Intra-muscular</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0078" ref-type="bibr">[78]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"><xref rid="tb1fn11" ref-type="table-fn">j</xref>MVA Vector</td><td valign="top">S protein</td><td valign="top">No</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0054" ref-type="bibr">[54]</xref></td></tr><tr><td valign="top"></td><td valign="top">Hamster</td><td valign="top"><xref rid="tb1fn10" ref-type="table-fn">k</xref>LAV</td><td valign="top"></td><td valign="top">Yes</td><td valign="top"><xref rid="tb1fn4" ref-type="table-fn">d</xref>Mild</td><td valign="top"><xref rid="bib0079" ref-type="bibr">[79]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"><xref rid="tb1fn3" ref-type="table-fn">c</xref>WIV</td><td valign="top">No Adjuvant</td><td valign="top">Yes</td><td valign="top"><xref rid="tb1fn4" ref-type="table-fn">d</xref>Mild</td><td valign="top"><xref rid="bib0080" ref-type="bibr">[80]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">AS01</td><td valign="top">Yes</td><td valign="top"><xref rid="tb1fn4" ref-type="table-fn">d</xref>Mild</td><td valign="top"><xref rid="bib0080" ref-type="bibr">[80]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top">Subunit</td><td valign="top">S protein trimer</td><td valign="top"></td><td valign="top"></td><td valign="top"></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">No Adjuvant</td><td valign="top">Yes</td><td valign="top">No</td><td valign="top"><xref rid="bib0081" ref-type="bibr">[81]</xref></td></tr><tr><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top">Alum</td><td valign="top">Yes</td><td valign="top">No</td><td valign="top"><xref rid="bib0081" ref-type="bibr">[81]</xref></td></tr><tr><td valign="top"></td><td valign="top">NHP</td><td valign="top"><xref rid="tb1fn11" ref-type="table-fn">j</xref>MVA Vector</td><td valign="top">S protein</td><td valign="top">Yes</td><td valign="top">Yes</td><td valign="top"><xref rid="bib0041" ref-type="bibr">[41]</xref></td></tr></tbody></table><table-wrap-foot><fn id="tb1fn1"><label>a</label><p id="notep0001">Protective - decrease in lung viral titer and/or mortality post-viral challenge</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb1fn2"><label>b</label><p id="notep0002">Immunopathology – histological evidence of damage or cellular (esp. eosinophil) infiltration in the airways</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb1fn3"><label>c</label><p id="notep0003">WIV – Whole Inactivated Virus</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb1fn4"><label>d</label><p id="notep0004">Minor Immunopathology and trace infiltrates observed</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb1fn5"><label>e</label><p id="notep0005">VEE – Venezuelan Equine Encephalitis</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb1fn6"><label>f</label><p id="notep0006">VV – recombinant Vaccinia Virus</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb1fn7"><label>g</label><p id="notep0007">VLP – Virus Like Particle</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb1fn8"><label>h</label><p id="notep0008">FCA – Freund's complete adjuvant</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb1fn9"><label>i</label><p id="notep0009">Ad Vector – Adenovirus Vector</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb1fn10"><label>j</label><p id="notep0010">MVA – Modified Vaccinia Virus Ankara</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb1fn11"><label>k</label><p id="notep0011">LAV – Live Attenuated Virus</p></fn></table-wrap-foot></table-wrap></p><p id="para0017">Another method of risk mitigation draws upon the lessons learned from cases of vaccine-induced ADE. The vaccines for RSV and measles that could give rise to ADE were both formalin-inactivated vaccines that generated Th2-skewed responses <xref rid="bib0062" ref-type="bibr">[62]</xref>. Similar evidence has been observed in animal studies with CoV vaccine candidates, where vaccines that skew towards a Th1 response elicited protection against both viral infection and immunopathology [<xref rid="bib0056" ref-type="bibr">56</xref>,<xref rid="bib0063" ref-type="bibr">63</xref>]. Vaccines that stimulate Th1 immunity with a strong T cell response component appears to be the way forward. <xref rid="tbl0002" ref-type="table">Table 2</xref>summarizes the evidence that T cells may mitigate the risk of immune enhancement in other viral infections. However, an important point of consideration is that the elicitation of T cell responses is not a panacea for vaccine development, as excessive T cell responses can also result in immunopathology [<xref rid="bib0064" ref-type="bibr">64</xref>,<xref rid="bib0065" ref-type="bibr">65</xref>].<table-wrap position="float" id="tbl0002"><label>Table 2</label><caption><p>Mitigation of ADE by T cell responses.</p></caption><alt-text id="alt0003">Table 2</alt-text><table frame="hsides" rules="groups"><thead><tr><th valign="top">Host</th><th valign="top">Virus</th><th valign="top">Model</th><th valign="top">Protective effect</th><th valign="top">Ref.</th></tr></thead><tbody><tr><td valign="top">Human</td><td valign="top"><xref rid="tb2fn3" ref-type="table-fn">c</xref>ZIKV</td><td valign="top"><xref rid="tb2fn3" ref-type="table-fn">c</xref>ZIKV-immune individuals stratified by <xref rid="tb2fn3" ref-type="table-fn">c</xref>DENV immunity</td><td valign="top">Broader, greater T cell responses Higher <xref rid="tb2fn7" ref-type="table-fn">g</xref>nAb titers Lower ADE</td><td valign="top"><xref rid="bib0082" ref-type="bibr">[82]</xref></td></tr><tr><td valign="top">Human</td><td valign="top"><xref rid="tb2fn4" ref-type="table-fn">d</xref>DENV</td><td valign="top"><xref rid="tb2fn4" ref-type="table-fn">d</xref>DENV ADE on heterologous <sup>4</sup>DENV immune individuals</td><td valign="top">IFN-γ suppresses ADE Addition of anti-IFN-γ <xref rid="tb2fn7" ref-type="table-fn">g</xref>nAb increases ADE</td><td valign="top"><xref rid="bib0083" ref-type="bibr">[83]</xref></td></tr><tr><td valign="top"><xref rid="tb2fn1" ref-type="table-fn">a</xref>AG129 mice</td><td valign="top"><xref rid="tb2fn4" ref-type="table-fn">d</xref>DENV</td><td valign="top">UV-inactivated <xref rid="tb2fn4" ref-type="table-fn">d</xref>DENV + alum vaccination</td><td valign="top">Transferred CD8<sup>+</sup> T cells protect mice even under ADE conditions</td><td valign="top"><xref rid="bib0084" ref-type="bibr">[84]</xref></td></tr><tr><td valign="top"><xref rid="tb2fn2" ref-type="table-fn">b</xref>A129 mice</td><td valign="top"><xref rid="tb2fn4" ref-type="table-fn">d</xref>DENV</td><td valign="top">T cell transfer from immunized mice</td><td valign="top">Transferred CD8<sup>+</sup> T cells protect mice even under ADE conditions</td><td valign="top"><xref rid="bib0085" ref-type="bibr">[85]</xref></td></tr><tr><td valign="top">Cats</td><td valign="top"><xref rid="tb2fn5" ref-type="table-fn">e</xref>FIPV</td><td valign="top">Peptide vaccine + CpG adjuvant</td><td valign="top">Reduced clinical symptoms<break></break>Improved survival<break></break>Protection only observed under low dose immunization</td><td valign="top"><xref rid="bib0086" ref-type="bibr">[86]</xref></td></tr><tr><td valign="top">BALB/c mice</td><td valign="top"><xref rid="tb2fn6" ref-type="table-fn">f</xref>RSV</td><td valign="top">DNA vaccine with additional immunogenic CpG motifs</td><td valign="top">Higher <xref rid="tb2fn7" ref-type="table-fn">g</xref>nAb titers<break></break>Th1-biased cytokine response</td><td valign="top"><xref rid="bib0087" ref-type="bibr">[87]</xref></td></tr><tr><td valign="top">BALB/c mice</td><td valign="top"><xref rid="tb2fn6" ref-type="table-fn">f</xref>RSV</td><td valign="top">Adenoviral vaccine vector</td><td valign="top">Higher <xref rid="tb2fn7" ref-type="table-fn">g</xref>nAb titers<break></break>Th1-biased cytokine response<break></break>Memory CD8<sup>+</sup> T cells generated</td><td valign="top"><xref rid="bib0088" ref-type="bibr">[88]</xref></td></tr><tr><td valign="top">BALB/c mice</td><td valign="top"><xref rid="tb2fn6" ref-type="table-fn">f</xref>RSV</td><td valign="top">DNA vaccine</td><td valign="top">Higher <xref rid="tb2fn7" ref-type="table-fn">g</xref>nAb titers</td><td valign="top"><xref rid="bib0089" ref-type="bibr">[89]</xref></td></tr></tbody></table><table-wrap-foot><fn id="tb2fn1"><label>a</label><p id="notep0012">Ifnar<sup>−/−</sup>Ifngr<sup>−/−</sup> mice on 129/Sv genetic background</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb2fn2"><label>b</label><p id="notep0013">Ifnar<sup>−/−</sup> mice on 129/Sv genetic background</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb2fn3"><label>c</label><p id="notep0014">Zika virus</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb2fn4"><label>d</label><p id="notep0015">Dengue virus</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb2fn5"><label>e</label><p id="notep0016">Feline Infectious peritonitis virus</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb2fn6"><label>f</label><p id="notep0017">Respriatory syncytial virus</p></fn></table-wrap-foot><table-wrap-foot><fn id="tb2fn7"><label>g</label><p id="notep0018">Neutralizing antibody</p></fn></table-wrap-foot></table-wrap></p></sec><sec id="sec0010"><label>4.2</label><title>Hyperimmune globulin therapy</title><p id="para0018">Extending experimental findings of CoV in animal models <xref rid="bib0041" ref-type="bibr">[41]</xref> to infer the risk of antibody-enhanced immunopathology in humans is more nuanced. There are likely major differences between vaccine-induced vs infection-induced antibodies. It is well known that innate immune response drives adaptive immune responses [<xref rid="bib0046" ref-type="bibr">46</xref>,<xref rid="bib0066" ref-type="bibr">66</xref>,<xref rid="bib0067" ref-type="bibr">67</xref>]. As SARS-CoV-2 infection is known to induce cytokine and chemokine expression, convalescent Covid-19 patients would likely produce antibodies that are qualitatively and quantitatively different to those elicited by vaccination alone. Although vaccines could also elicit innate immune responses, the magnitude would likely be significantly lower than those found in acutely ill Covid-19 patients since the disease is probably mediated by a pro-inflammatory cytokine response <xref rid="bib0068" ref-type="bibr">[68]</xref>. Moreover, the antigenic burden of wild-type SARS-CoV-2 infection can be expected to be significantly greater than those derived from vaccination. The level of such antigenic burden is known to drive adaptive immune responses, including neutralizing antibody titers [<xref rid="bib0045" ref-type="bibr">45</xref>,<xref rid="bib0069" ref-type="bibr">69</xref>]. Consequently, extending findings from vaccine studies to infer the risk from hyperimmune globulin ignore the possibility of differences between the quality and titer of antibodies produced from infection and vaccination. This same explanation was also found to underpin how inactivated measles vaccination increases the risk of atypical pneumonia <xref rid="bib0031" ref-type="bibr">[31]</xref>.</p><p id="para0019">Early anecdotal reports that infusion of convalescent plasma to acutely ill Covid-19 patients suggest the potential of hyperimmune globulin as a treatment to halt the progression of infection to severe pulmonary disease. Hyperimmune globulin treatment, besides inhibiting viral infection, could also downregulate pro-inflammatory responses and reduce disease severity in Covid-19 patients. Intravenous immunoglobulin (IVIG) infusion is associated with anti-inflammatory responses <xref rid="bib0070" ref-type="bibr">[70]</xref>, including those from viral infection <xref rid="bib0071" ref-type="bibr">[71]</xref>. Mechanistically, how this anti-inflammatory effect is mediated remains to be fully defined. High dose antibodies could bind a number of different inhibitory receptors, including the inhibitory Fc gamma receptor IIB (FcγRIIB) [<xref rid="bib0033" ref-type="bibr">33</xref>,<xref rid="bib0072" ref-type="bibr">72</xref>], FcγRIIC [<xref rid="bib0073" ref-type="bibr">73</xref>,<xref rid="bib0074" ref-type="bibr">74</xref>] or other receptors <xref rid="bib0075" ref-type="bibr">[75]</xref> to induce the anti-inflammatory response. Regardless of the mechanism, the presence of neutralizing SARS-CoV-2 antibodies as well as high concentration of total antibodies could produce anti-inflammatory rather than the postulated immunopathology enhancement effects in Covid-19 patients to improve prognosis.</p></sec></sec><sec id="sec0011"><label>5</label><title>Concluding remarks</title><p id="para0020">While experimental evidence to prove or disprove immune enhancement as a pathogenic basis of severe Covid-19 remains to be obtained, current knowledge on the mechanism of ADE and immune enhancement collectively suggest that the risk that hyperimmune globulin or a highly efficacious vaccine pose to exacerbating disease is low. Most descriptions of ADE occur in experimental settings without strong clinical support. Thus, until animal models that accurately capture the pathological features of Covid-19 has been developed and validated, filling the gap in clinical evidence for immune enhancement should be a priority on the research agenda (<xref rid="tbl0003" ref-type="table">Box 1</xref>).<table-wrap position="float" id="tbl0003"><label>Box 1</label><caption><p>Investigations needed to further our understanding of the risks of immune enhancement.</p></caption><alt-text id="alt0004">Box 1</alt-text><table frame="hsides" rules="groups"><tbody><tr><td valign="top">The current Covid-19 pandemic with exponential rise in disease cases and deaths urgently calls for both treatment options and efficacious vaccines. However, it cannot be ignored that enhanced immunopathology has been observed with other coronaviruses in animal models, albeit in the absence of convincing clinical evidence. Therefore, in parallel with phase I trials, we suggest urgent clinical evidence to address the gap in clinical evidence for immune enhancement. A list of studies are described below:</td></tr><tr><td valign="top"><list list-type="simple" id="celist0001"><list-item id="celistitem0001"><label>•</label><p id="para0044">Systematic post-mortem examination with deep immunological and molecular profiling to define the pathology of fatal Covid-19 cases.</p></list-item></list></td></tr><tr><td valign="top"><list list-type="simple" id="celist0002"><list-item id="celistitem0002"><label>•</label><p id="para0045">Prospectively enrolled cohort study to determine pre-infection and early post-illness onset immune correlates of Covid-19 disease outcome.</p></list-item></list></td></tr><tr><td valign="top"><list list-type="simple" id="celist0003"><list-item id="celistitem0003"><label>•</label><p id="para0046">Develop animal models that replicates the important pathological features found in systematic post-mortem examination of fatal Covid-19 cases.</p></list-item></list></td></tr></tbody></table></table-wrap></p></sec><sec id="sec0012"><label>6</label><title>Outstanding Questions</title><p id="para0021">Large gaps exist in our understanding of the risk of immunopathology with SARS-CoV-2, the epidemiological risk factors, the mechanism and immune mediators of pathology during CoV infections. Clinical studies, preferably in prospectively enrolled cohorts, coupled with detailed investigations into the pre-infection and post-infection correlates of severe Covid-19. Controlled human infection models, perhaps using less virulent CoVs, including human CoV OC43, could also provide a safe avenue to explore the possibility of immune enhancement in CoV infections.</p></sec><sec id="sec0013"><label>7</label><title>Search strategy and selection criteria</title><p id="para0022">Data was identified for this review using the following search terms on PubMed: antibody dependent enhancement, ADE, antibody dependent immunopathology, coronavirus, SARS, MERS, SARS-CoV-2, Covid-19, vaccines, treatment, therapeutics, hyperimmune globulin, T cells, antibodies, cross-reactive antibodies. Only articles published in English from 1965 till March 2020 were included.</p></sec><sec sec-type="COI-statement"><title>Declaration of Competing Interest</title><p id="para0025">The authors declare no conflict of interest.</p></sec></body><back><ref-list id="cebibl1"><title>References</title><ref id="bib0001"><label>1</label><element-citation publication-type="book" id="sbref0001"><person-group person-group-type="author"><collab>WHO</collab></person-group><person-group person-group-type="editor"><name><surname>WHO</surname></name></person-group><source>Coronavirus disease 2019 (COVID-19) Situation Report 72</source><year>2020</year><publisher-name>WHO</publisher-name><publisher-loc>Geneva</publisher-loc><comment>editor. 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(Senior Investigator) administered by the National Medical Research Council, Singapore. No other funding was received for this review.</p></sec><sec id="sec0015"><title>Author contributions</title><p id="para0024">RdA, SC, ESG and EEO contributed to the conceptualization and creation of the original and final drafts of the manuscript.</p></sec></ack></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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