High resolution profiling of pathways of escape for SARS-CoV-2 spike-binding antibodies

Garrett, Meghan; Galloway, Jared; Chu, Helen Y.; Itell, Hannah L.; Stoddard, Caitlin I.; Wolf, Caitlin R; Logue, Jennifer K.; McDonald, Dylan; Matsen, F. A.; Overbaugh, Julie

doi:10.1101/2020.11.16.385278

Cited by 15 publications

(20 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The results presented here appear to be of immediate interest in relation to the vaccination campaign against SARS-Cov-2 that is beginning at the time of this writing. However, although diversification of the virus is apparent 24-26 and the potential for escape is being actively investigated 5,6,27,28 , it cannot be ruled out that all escape variants have a substantially reduced infectivity, represented by β << 1 , in which case the highest possible vaccination rate will be optimal and the benefits specific to post-vaccination contact limitation could be negligible.…”

Section: Limitationsmentioning

confidence: 99%

Substantial Impact of Post Vaccination Contacts on Cumulative Infections during Viral Epidemics

Rochman

Wolf

Koonin

2020

Preprint

View full text Add to dashboard Cite

BackgroundThe start of 2021 will be marked by a global vaccination campaign against the novel coronavirus SARS-CoV-2. Formulating an optimal distribution strategy under social and economic constraints is challenging. Optimal distribution is additionally constrained by the potential emergence of vaccine resistance. Analogous to chronic low-dose antibiotic exposure, recently inoculated individuals who are not yet immune play an outsized role in the emergence of resistance. Classical epidemiological modelling is well suited to explore how the behavior of the inoculated population impacts the total number of infections over the entirety of an epidemic.MethodsA deterministic model of epidemic evolution is analyzed, with 7 compartments defined by their relationship to the emergence of vaccine-resistant mutants and representing three susceptible populations, three infected populations, and one recovered population. This minimally computationally intensive design enables simulation of epidemics across a broad parameter space. The results are used to identify conditions minimizing the cumulative number of infections.ResultsWhen an escape variant is only modestly less infectious than the originating strain within a naïve population, there exists an optimal rate of vaccine distribution. Exceeding this rate increases the cumulative number of infections due to vaccine escape. Analysis of the model also demonstrates that inoculated individuals play a major role in the mitigation or exacerbation of vaccine-resistant outbreaks. Modulating the rate of host-host contact for the inoculated population by less than an order of magnitude can alter the cumulative number of infections by more than 20%.ConclusionsMathematical modeling shows that optimization of the vaccination rate and limiting post-vaccination contacts can affect the course of an epidemic. Given the relatively short window between inoculation and the acquisition of immunity, these results might merit consideration for an immediate, practical public health response.

show abstract

Section: Limitationsmentioning

confidence: 99%

Substantial Impact of Post Vaccination Contacts on Cumulative Infections during Viral Epidemics

Rochman

Wolf

Koonin

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Diversification of the virus is apparent [31][32][33] and, as discussed above, antibody evasion had been investigated early on and demonstrated prior to mass vaccination. 5,6,[18][19][20][21][22][23]34,35 The existence of these variants indicates that evolution of the SARS-CoV-2 antigen is not subject to constraints that would prohibit reduction in antibody affinity to achieve immune evasion, while maintaining host receptor affinity sufficient for infection.…”

Section: Discussionmentioning

confidence: 99%

Substantial impact of post-vaccination contacts on cumulative infections during viral epidemics

Rochman¹,

Wolf

Koonin

2021

F1000Res

View full text Add to dashboard Cite

Background: The start of 2021 was marked by the initiation of a global vaccination campaign against the novel coronavirus SARS-CoV-2. Formulating an optimal distribution strategy under social and economic constraints is challenging. Optimal distribution is additionally constrained by the potential emergence of vaccine resistance. Analogous to chronic low-dose antibiotic exposure, recently inoculated individuals who are not yet immune play an outsized role in the emergence of resistance. Classical epidemiological modelling is well suited to explore how the behavior of the inoculated population impacts the total number of infections over the entirety of an epidemic. Methods: A deterministic model of epidemic evolution is analyzed, with seven compartments defined by their relationship to the emergence of vaccine-resistant mutants and representing three susceptible populations, three infected populations, and one recovered population. This minimally computationally intensive design enables simulation of epidemics across a broad parameter space. The results are used to identify conditions minimizing the cumulative number of infections. Results: When an escape variant is only modestly less infectious than the originating strain within a naïve population, there exists an optimal rate of vaccine distribution. Exceeding this rate increases the cumulative number of infections due to vaccine escape. Analysis of the model also demonstrates that inoculated individuals play a major role in the mitigation or exacerbation of vaccine-resistant outbreaks. Modulating the rate of host–host contact for the inoculated population by less than an order of magnitude can alter the cumulative number of infections by more than 20%. Conclusions: Mathematical modeling shows that optimization of the vaccination rate and limiting post-vaccination contacts can perceptibly affect the course of an epidemic. The consideration of limitations on post-vaccination contacts remains relevant for the entire duration of any vaccination campaign including the current status of SARS-CoV-2 vaccination.

show abstract

“…6B). Among the most strongly bound epitopes were those in the vicinity of heptad repeat 2 (HR2) and the fusion peptide (FP) which are also widespread in sera from infected humans (Garrett et al 2020;Poh et al 2020;Shrock et al 2020). We identified only one strongly binding internal linear epitope, which is centered around residue 991 in a helix, and which bound sera from one of the S-R/PP immunized mice.…”

Section: Sera Contain Antibodies Against Linear Epitopes From Surfacementioning

confidence: 96%

SARS-CoV-2 spike protein arrested in the closed state induces potent neutralizing responses

Carnell

Ciazynska

Wells

et al. 2021

Preprint

View full text Add to dashboard Cite

The majority of SARS-CoV-2 vaccines in use or in advanced clinical development are based on the viral spike protein (S) as their immunogen. S is present on virions as pre-fusion trimers in which the receptor binding domain (RBD) is stochastically open or closed. Neutralizing antibodies have been described that act against both open and closed conformations. The long-term success of vaccination strategies will depend upon inducing antibodies that provide long-lasting broad immunity against evolving, circulating SARS-CoV-2 strains, while avoiding the risk of antibody dependent enhancement as observed with other Coronavirus vaccines. Here we have assessed the results of immunization in a mouse model using an S protein trimer that is arrested in the closed state to prevent exposure of the receptor binding site and therefore interaction with the receptor. We compared this with a range of other modified S protein constructs, including representatives used in current vaccines. We found that all trimeric S proteins induce a long-lived, strongly neutralizing antibody response as well as T-cell responses. Notably, the protein binding properties of sera induced by the closed spike differed from those induced by standard S protein constructs. Closed S proteins induced more potent neutralising responses than expected based on the degree to which they inhibit interactions between the RBD and ACE2. These observations suggest that closed spikes recruit different, but equally potent, virus-inhibiting immune responses than open spikes, and that this is likely to include neutralizing antibodies against conformational epitopes present in the closed conformation. Together with their improved stability and storage properties we suggest that closed spikes may be a valuable component of refined, next-generation vaccines.

show abstract

High resolution profiling of pathways of escape for SARS-CoV-2 spike-binding antibodies

Cited by 15 publications

References 59 publications

Substantial Impact of Post Vaccination Contacts on Cumulative Infections during Viral Epidemics

Substantial Impact of Post Vaccination Contacts on Cumulative Infections during Viral Epidemics

Substantial impact of post-vaccination contacts on cumulative infections during viral epidemics

SARS-CoV-2 spike protein arrested in the closed state induces potent neutralizing responses

Contact Info

Product

Resources

About