COVID-19 vaccine design: the Janus face of immune enhancement

Hotez, Peter J.; Corry, David B.; Bottazzi, María Elena

doi:10.1038/s41577-020-0323-4

Cited by 174 publications

(197 citation statements)

References 10 publications

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“…A previous study employing four different candidate vaccines against SARS-CoV, all of them with and without alum adjuvants successfully elicited neutralizing antibodies and conferred protection against infection; however, tissue damage due to immunopathology was also observed from infiltrating lymphocytes [12]. Historical evidence from animal models suggests, vaccine-primed Th2 and Th17 responses may be associated with immunopathology referred to as vaccine-associated enhanced respiratory disease (VAERD) [13]; therefore, extra caution must be taken in the choice of adjuvants. Synthetic oligodeoxynucleotides with CpG motifs (CpG ODN) are agonists for TLR9 and mimic the activity of naturally occurring CpG motifs found in bacterial DNA.…”

Section: Introductionmentioning

confidence: 99%

Development of CpG-adjuvanted stable prefusion SARS-CoV-2 spike antigen as a subunit vaccine against COVID-19

Kuo

Lin²,

Coffman

et al. 2020

Preprint

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The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 is a worldwide health emergency. The immense damage done to public health and economies has prompted a global race for cures and vaccines. In developing a COVID-19 vaccine, we applied technology previously used for MERS-CoV to produce a prefusion-stabilized SARS-CoV-2 spike protein by adding two proline substitutions at the top of the central helix (S-2P). To enhance immunogenicity and mitigate the potential vaccine-induced immunopathology, CpG 1018, a Th1-biasing synthetic toll-like receptor 9 (TLR9) agonist was selected as an adjuvant candidate. S-2P was combined with various adjuvants, including CpG 1018, and administered to mice to test its effectiveness in eliciting anti-SARS-CoV-2 neutralizing antibodies. S-2P in combination with CpG 1018 and aluminum hydroxide (alum) was found to be the most potent immunogen and induced high titer of spike-specific antibodies in sera of immunized mice. The neutralizing abilities were measured with pseudotyped lentivirus reporter or live wild-type SARS-CoV-2 with reciprocal inhibiting dilution (ID50) titers of 5120 and 2560, respectively. In addition, the antibodies elicited were also able to neutralize pseudovirus containing the spike protein of the recent dominating variant D614G. A marked Th-1 dominant response was noted from cytokines secreted by splenocytes of mice immunized with CpG 1018 and alum. No vaccine-related serious adverse effects were found in the dose-ranging study in rats administered single- or two-dose regimens. These data support continued development of CHO-derived S-2P formulated with CpG 1018/alum as a broadly protective candidate vaccine to prevent COVID-19 disease.

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Section: Introductionmentioning

confidence: 99%

Development of CpG-adjuvanted stable prefusion SARS-CoV-2 spike antigen as a subunit vaccine against COVID-19

Kuo

Lin²,

Coffman

et al. 2020

Preprint

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“…This cross-reactivity does not necessarily mediate an enhanced protection against COVID-19 [29]. In contrast, it may promote ADE of the disease [18][19][20] [30,31]. Whether other 'common cold' coronaviruses negatively contribute to the severity of COVID-19 through ADE towards the end of the 'common cold' season or whether exposure to these coronaviruses provides T cellmediated protection that prevents the disease from developing into its severe or fatal forms remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…These ndings suggested a T cell-mediated cross-reactivity between circulating 'common cold' coronaviruses and SARS-CoV-2. This cross-reactivity could be responsible for either enhanced protection against COVID-19 [15][16][17] or, in contrast, for antibody-dependent enhancement (ADE) of COVID-19 [18][19][20][21].…”

Section: Cd4 T Cells Of Prostate Cancer Patients Have Decreased Immunmentioning

confidence: 99%

CD4 T cells of prostate cancer patients have decreased immune responses to antigens derived from SARS-CoV-2 spike glycoprotein

Taborska

Střížová

Stakheev

et al. 2020

Preprint

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The adaptive immune response to severe acute respiratory coronavirus 2 (SARS-CoV-2) is important for vaccine development and coronavirus disease 2019 (COVID-19) recovery. Men and cancer patients have been reported to be at higher risks of contracting the virus and developing severe COVID-19. Prostate cancer (PCa) may be associated with both of these risks. We show that CD4+ T cells of SARS-CoV-2-unexposed patients with hormone-refractory (HR) metastatic PCa have substantially decreased CD4+ T cell immune responses to antigens from SARS-CoV-2 spike glycoprotein but not from the spiked glycoprotein of the 'common cold'-associated human coronavirus 229E (HCoV-229E) as compared with healthy male volunteers. Moreover, the HCoV-229E spike glycoprotein antigen-elicited CD4+ T cell immune responses cross-reacted with the SARS-CoV-2 spiked glycoprotein antigens. PCa patients may not respond to the vaccination, and the cross-reactivity can mediate antibody-dependent enhancement (ADE) of COVID-19. These findings highlight the potential for increased vulnerability of PCa patients to COVID-19.

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“…40,41,42,43 Therapeutics that mimic ACE2 and shield this key epitope are likely to bias antibody formation towards off-target sites, which could contribute to antibody-dependent enhancement (ADE), vaccine-associated enhanced respiratory distress (VAERD), and a host of other immunological issues upon repeat viral challenge. 44,45,46,47,48,49,50,51,52,52 With SARS-CoV-1, a marked lack of peripheral memory B cell responses was observed in patients 6 years following infection. 53 These key issues are also important to consider in vaccine development, as there is precedent for enhanced respiratory disease in vaccinated animals with SARS-CoV-1.…”

Section: Discussionmentioning

confidence: 99%

Peptide Antidotes to SARS-CoV-2 (COVID-19)

Watson

Ferreira

Hwang

et al. 2020

Preprint

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The design of an immunogenic scaffold that serves a role in treating a pathogen, and can be rapidly and predictively modeled, has remained an elusive feat. Here, we demonstrate that SARS-BLOCK™ synthetic peptide scaffolds act as antidotes to SARS-CoV-2 spike protein-mediated infection of human ACE2-expressing cells. Critically, SARS-BLOCK™ peptides are able to potently and competitively inhibit SARS-CoV-2 S1 spike protein receptor binding domain (RBD) binding to ACE2, the main cellular entry pathway for SARS-CoV-2, while also binding to neutralizing antibodies against SARS-CoV-2. In order to create this potential therapeutic antidote-vaccine, we designed, simulated, synthesized, modeled epitopes, predicted peptide folding, and characterized behavior of a novel set of synthetic peptides. The biomimetic technology is modeled off the receptor binding motif of the SARS-CoV-2 coronavirus, and modified to provide enhanced stability and folding versus the truncated wildtype sequence. These novel peptides attain single-micromolar binding affinities for ACE2 and a neutralizing antibody against the SARS-CoV-2 receptor binding domain (RBD), and demonstrate significant reduction of infection in nanomolar doses. We also demonstrate that soluble ACE2 abrogates binding of RBD to neutralizing antibodies, which we posit is an essential immune-evasive mechanism of the virus. SARS-BLOCK™ is designed to “uncloak” the viral ACE2 coating mechanism, while also binding to neutralizing antibodies with the intention of stimulating a specific neutralizing antibody response. Our peptide scaffolds demonstrate promise for future studies evaluating specificity and sensitivity of immune responses to our antidote-vaccine. In summary, SARS-BLOCK™ peptides are a promising COVID-19 antidote designed to combine the benefits of a therapeutic and vaccine, effectively creating a new generation of prophylactic and reactive antiviral therapeutics whereby immune responses can be enhanced rather than blunted.

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COVID-19 vaccine design: the Janus face of immune enhancement

Cited by 174 publications

References 10 publications

Development of CpG-adjuvanted stable prefusion SARS-CoV-2 spike antigen as a subunit vaccine against COVID-19

Development of CpG-adjuvanted stable prefusion SARS-CoV-2 spike antigen as a subunit vaccine against COVID-19

CD4 T cells of prostate cancer patients have decreased immune responses to antigens derived from SARS-CoV-2 spike glycoprotein

Peptide Antidotes to SARS-CoV-2 (COVID-19)

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