Developing Vaccines for SARS-CoV-2 and Future Epidemics and Pandemics: Applying Lessons from Past Outbreaks

Billington, John; Deschamps, Isabelle; Erck, Stanley C.; Gerberding, Julie L.; Hanon, Emmanuel; Ivol, Sabrina; Shiver, John W.; Spencer, Julia; Hoof, Johan Van

doi:10.1089/hs.2020.0043

Cited by 32 publications

(27 citation statements)

References 16 publications

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“…An immediate goal for the current SARS-CoV-2 pandemic is to identify treatments, including passively administered neutralizing antibodies, that could ameliorate COVID-19 disease and improve survival (17,18). Another urgent priority is the development of a vaccine that could protect against SARS-CoV-2 infection (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

“…The SARS-CoV-2 spike glycoprotein (S gp) is the major target of virusneutralizing antibodies that are thought to be important for vaccine-induced protection (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). The SARS-CoV-2 S gp mediates the entry of the virus into host cells and influences tissue tropism and pathogenesis (22,23,(32)(33)(34)(35).…”

Section: Introductionmentioning

confidence: 99%

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Spike Glycoprotein and Host Cell Determinants of SARS-CoV-2 Entry and Cytopathic Effects

Nguyen

Zhang

Wang

et al. 2021

J Virol

105

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SARS-CoV-2, a betacoronavirus, is the cause of the COVID-19 pandemic. The SARS-CoV-2 spike (S) glycoprotein trimer mediates virus entry into host cells and cytopathic effects (syncytium formation). We studied the contribution of several S glycoprotein features to these functions, focusing on those that differ among related coronaviruses. Acquisition of the furin cleavage site by the SARS-CoV-2 S glycoprotein decreased virus stability and infectivity, but greatly enhanced syncytium-forming ability. Notably, the D614G change found in globally predominant SARS-CoV-2 strains increased infectivity, modestly enhanced responsiveness to the ACE2 receptor and susceptibility to neutralizing sera, and tightened association of the S1 subunit with the trimer. Apparently, these two features of the SARS-CoV-2 S glycoprotein, the furin cleavage site and D614G, have evolved to balance virus infectivity, stability, cytopathicity and antibody vulnerability. Although the endodomain (cytoplasmic tail) of the S2 subunit was not absolutely required for virus entry or syncytium formation, alteration of palmitoylated cysteine residues in the cytoplasmic tail decreased the efficiency of these processes. As proteolytic cleavage contributes to the activation of the SARS-CoV-2 S glycoprotein, we evaluated the ability of protease inhibitors to suppress S glycoprotein function. Matrix metalloprotease inhibitors suppressed S-mediated cell-cell fusion, but not virus entry. Synergy between inhibitors of matrix metalloproteases and TMPRSS2 suggests that both host proteases can activate the S glycoprotein during the process of syncytium formation. These results provide insights into SARS-CoV-2 S glycoprotein-host cell interactions that likely contribute to the transmission and pathogenicity of this pandemic agent. IMPORTANCE The development of an effective and durable SARS-CoV-2 vaccine is essential for combating the growing COVID-19 pandemic. The SARS-CoV-2 spike (S) glycoprotein is the main target of neutralizing antibodies elicited during virus infection or following vaccination. Knowledge of the spike glycoprotein evolution, function and interactions with host factors will help researchers to develop effective vaccine immunogens and treatments. Here we identify key features of the spike glycoprotein, including the furin cleavage site and the D614G natural mutation, that modulate viral cytopathic effects, infectivity and sensitivity to inhibition. We also identify two inhibitors of host metalloproteases that block S-mediated cell-cell fusion, a process that contributes to the destruction of the virus-infected cell.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spike Glycoprotein and Host Cell Determinants of SARS-CoV-2 Entry and Cytopathic Effects

Nguyen

Zhang

Wang

et al. 2021

J Virol

105

View full text Add to dashboard Cite

show abstract

“…The COVID-19 pandemic caused by the SARS-CoV-2 virus is a clear warning that new infectious diseases with pandemic potential can inflict high human and economic losses. In response to the crisis, regulatory agencies have made unprecedented strides to help get safe and reliable vaccinations to the market sooner [ 82 ]. Leaders must invest in evidence-based vaccine delivery strategies that generate demand, allocate, and distribute vaccines.…”

Section: The Future Of Vaccine Formulationsmentioning

confidence: 99%

Development of vaccine formulations: past, present, and future

D'Amico

Fontana

Chen

et al. 2021

Drug Deliv. and Transl. Res.

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The current situation, heavily influenced by the ongoing pandemic, puts vaccines back into the spotlight. However, the conventional and traditional vaccines present disadvantages, particularly related to immunogenicity, stability, and storage of the final product. Often, such products require the maintenance of a “cold chain,” impacting the costs, the availability, and the distribution of vaccines. Here, after a recall of the mode of action of vaccines and the types of vaccines currently available, we analyze the past, present, and future of vaccine formulation. The past focuses on conventional formulations, the present discusses the use of nanoparticles for vaccine delivery and as adjuvants, while the future presents microneedle patches as alternative formulation and administration route. Finally, we compare the advantages and disadvantages of injectable solutions, nanovaccines, and microneedles in terms of efficacy, stability, and patient-friendly design. Graphical abstract Different approaches to vaccine formulation development, the conventional vaccine formulations from the past, the current development of lipid nanoparticles as vaccines, and the near future microneedles formulations are discussed in this review.

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“…Poor treatment options and the exceptional high burden of COVID-19 on healthcare systems still demands radical preventive measures including travel restrictions, social distancing and lockdowns, resulting in the most severe global social and economic disruption since world war II ( Gossling et al, 2020 ; Dhama et al, 2020 ). Time-lines to bring a safe and efficacious vaccine for SARS-CoV-2 to market has been proposed to take 12–18 months under ideal circumstances ( Billington et al, 2020 ). Even if intense collaboration and resource allocation can speed up vaccine development it remains a challenge to get the product to the most vulnerable individuals in time.…”

Section: Introductionmentioning

confidence: 99%

TLR9 and COVID-19: A Multidisciplinary Theory of a Multifaceted Therapeutic Target

Bezemer

Garssen

2021

Front. Pharmacol.

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By mapping the clinical pathophysiology of the novel coronavirus disease 2019 (COVID-19) against insights from virology, immunology, genomics, epidemiology and pharmacology, it is here proposed that the pathogen recognition receptor called toll like receptor 9 (TLR9) might have a pivotal role in the pathogenesis of COVID-19. Severe Acute Respiratory Syndrome Coronavirus 2, is causing the greatest global social and economic disruption since world war II. Lack of a vaccine, lack of successful treatment and limitations of the healthcare workforce and resources needed to safeguard patients with severe COVID-19 on the edge of life, demands radical preventive measures. It is urgently needed to identify biomarkers and drug candidates so that vulnerable individuals can be recognized early and severe multi-organ complications can be prevented or dampened. The TLR9 COVID-19 hypothesis describes a mechanism of action that could explain a wide spectrum of manifestations observed in patients with severe COVID-19. The introduced hypothesis proposes biomarkers for identification of vulnerable individuals and positions TLR9 as a promising multifaceted intervention target for prevention and/or treatment of COVID-19. TLR9 agonists might have value as prophylactic vaccine adjuvants and therapeutic immune stimulators at the early onset of disease. Additionally, in this current manuscript it is proposed for the first time that TLR9 could be considered as a target of “inhibition” aimed to dampen hyperinflammation and thrombotic complications in vulnerable patients that are at risk of developing late stages of COVID-19. The readily availability of TLR9 modulating drug candidates that have reached clinical testing for other disorders could favor a fast track development scenario, an important advantage under the current high unmet medical need circumstances regarding COVID-19.

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Developing Vaccines for SARS-CoV-2 and Future Epidemics and Pandemics: Applying Lessons from Past Outbreaks

Cited by 32 publications

References 16 publications

Spike Glycoprotein and Host Cell Determinants of SARS-CoV-2 Entry and Cytopathic Effects

Spike Glycoprotein and Host Cell Determinants of SARS-CoV-2 Entry and Cytopathic Effects

Development of vaccine formulations: past, present, and future

TLR9 and COVID-19: A Multidisciplinary Theory of a Multifaceted Therapeutic Target

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