Rustom Antia’s research while affiliated with Emory University and other places

In vivo in infection, virions are constantly produced and die rapidly. In contrast, most antibody binding assays do not include such features. Motivated by this, we considered virions with n = 100 binding sites in simple mathematical models with and without the production of virions. In the absence of viral production, at steady state, the distribution of virions by the number of sites bound is given by a binomial distribution, with the proportion being a simple function of antibody affinity (Kon/Koff) and concentration; this generalizes to a multinomial distribution in the case of two or more kinds of antibodies. In the presence of viral production, the role of affinity is replaced by an infection analog of affinity (IAA), with IAA = Kon/(Koff + dv + r), where dv is the virus decay rate and r is the infection growth rate. Because in vivo dv can be large, the amount of binding as well as the effect of Koff on binding are substantially reduced. When neutralization is added, the effect of Koff is similarly small which may help explain the relatively high Koff reported for many antibodies. We next show that the n+2-dimensional model used for neutralization can be simplified to a 2-dimensional model. This provides some justification for the simple models that have been used in practice. A corollary of our results is that an unexpectedly large effect of Koff in vivo may point to mechanisms of neutralization beyond stoichiometry. Our results suggest reporting Kon and Koff separately, rather than focusing on affinity, until the situation is better resolved both experimentally and theoretically.

Severe acute respiratory syndrome coronavirus 2 mRNA vaccination has reduced effectiveness in certain immunocompromised individuals. However, the cellular mechanisms underlying these defects, as well as the contribution of disease-induced cellular abnormalities, remain largely unexplored. In this study, we conducted a comprehensive serological and cellular analysis of patients with autoimmune systemic lupus erythematosus (SLE) who received the Wuhan-Hu-1 monovalent mRNA coronavirus disease 2019 vaccine. Our findings revealed that patients with SLE exhibited reduced avidity of anti-receptor-binding domain antibodies, leading to decreased neutralization potency and breadth. We also observed a sustained anti-spike response in IgD⁻CD27⁻ ‘double-negative (DN)’ DN2/DN3 B cell populations persisting during memory responses and with greater representation in the SLE cohort. Additionally, patients with SLE displayed compromised anti-spike T cell immunity. Notably, low vaccine efficacy strongly correlated with higher values of a newly developed extrafollicular B and T cell score, supporting the importance of distinct B cell endotypes. Finally, we found that anti-BAFF blockade through belimumab treatment was associated with poor vaccine immunogenicity due to inhibition of naive B cell priming and an unexpected impact on circulating T follicular helper cells.

Introduction Patients with B cell malignancies remain at high risk of morbidity and mortality from respiratory viruses like SARS-CoV-2. These patients often receive B cell-depleting agents in combination with chemotherapy as part of their cancer treatment, impairing their subsequent capacity to generate antibody responses to infection and vaccination. However, less is known about the effects of these aggressive treatments on already acquired humoral immunity in this population. Objective To determine the effect of frontline chemoimmunotherapy with anti-CD20 antibodies on established antibody titers against SARS-CoV-2, measles, and rubella over time in patients with newly diagnosed aggressive B cell non-Hodgkin lymphoma (aNHL). Methods Patients with a new diagnosis of aNHL were enrolled after informed consent. Serial blood samples were obtained before, during, and up to 1 year after treatment with regimens containing an anti-CD20 antibody + multiagent chemotherapy. IgG binding titers against the SARS-CoV-2 nucleocapsid (N) protein and the spike protein of several SARS-CoV-2 variants were measured with a multiplex assay. Live virus neutralization titers against SARS-CoV-2 variants over time were also measured. IgG titers against measles and rubella were measured by ELISA. Antibody decay half-lives were calculated using exponential model. Clinical information was abstracted from the electronic medical record and correlated with antibody responses. Results A total of 42 individuals were enrolled (33 with aNHL, 9 healthy donor controls). For the aNHL group, mean age was 59.7, 51.5% were male, and 39.4% non-white. Mean number of vaccine doses was 3 with a mean of 199 days between last vaccine and cycle 1 of lymphoma-directed therapy. All patients received rituximab as their anti-CD20 antibody and only 2 patients did not receive an anthracycline. Before treatment (baseline), 56.5% of aNHL patients did not show anti-N antibodies to indicate prior infection. Greater variability in IgG binding titers against wild-type (WT) spike protein and significantly lower neutralization titers were observed in aNHL at baseline vs controls (mean titer 1227 vs 1822 AU/mL, p<0.05). Median binding titers against BA.5 and XBB.1.5 spike was 5.3- and 8.3-fold lower than WT, respectively (vs 4.0- and 7.2-fold in control, respectively). Median anti-WT spike binding titers decreased by 2.5-, 3.4-, and 6.1-fold after 3-, 9- , and 12-months from initiation of chemoimmunotherapy, respectively while titers in controls decreased 1.1-fold over a similar period. After excluding 2 patients with very low anti-WT spike titers before aNHL treatment, the half-life for anti-WT spike was 192 days in aNHL patients vs 444 days in controls (p<0.001). No statistically significant increase in anti-spike titers was seen in the 16 patients who received an additional SARS-CoV-2 vaccine within the first year of treatment initiation. Multivariable analyses for factors associated with more rapid decay will be presented. Antibody titers vs SARS-CoV-2 are known to wane over time. Thus, to determine the effect of aNHL treatment on long-term humoral immunity, IgG titers against measles and rubella were measured, as these antibodies show remarkable stability over time in healthy individuals, and the likelihood of infection while on study was low. Baseline titers against measles and rubella did not differ significantly between controls and aNHL patients. Anti-measles and rubella titers showed <2-fold decrease during the study period in aNHL patients and no decline in control. Conclusion In patients with newly diagnosed aNHL, preexisting antibody titers vs SARS-CoV-2, measles, and rubella, were largely preserved during lymphoma-directed treatment. However, an accelerated rate of decay was observed for anti-spike IgG during the first year after completion of aNHL therapy. Neutralization activity against newer SARS-CoV-2 variants was low throughout the study period. Our data highlight the need for new mechanisms to protect these immunocompromised patients against current and emerging SARS-CoV-2 strains.

Reinfections with respiratory viruses such as influenza viruses and coronaviruses are thought to be driven by ongoing antigenic immune escape in the viral population. However, this does not explain why antigenic variation is frequently observed in these viruses relative to viruses such as measles that undergo systemic replication. Here, we suggest that the rapid rate of waning immunity in the respiratory tract is the key driver of antigenic evolution in respiratory viruses. Waning immunity results in hosts with immunity levels that protect against homologous reinfection but are insufficient to protect against infection with a heterologous, antigenically different strain. As such, when partially immune hosts are present at a high enough density, an immune escape variant can invade the viral population even though that variant cannot infect fully immune hosts. Invasion can occur even when the variant's immune escape mutation incurs a fitness cost, and we expect the expanding mutant population will evolve compensatory mutations that mitigate this cost. Thus the mutant lineage should replace the wild-type, and as immunity to it builds, the process will repeat. Our model provides a new explanation for the pattern of successive emergence and replacement of antigenic variants that has been observed in many respiratory viruses. We discuss testable predictions of our model relative to others for understanding the drivers of antigenic evolution in these and other respiratory viruses.

In vivo in infection, virions are constantly produced and die rapidly. In contrast, most antibody binding assays do not include such features. Motivated by this, we considered virions with n=100 binding sites in simple mathematical models with and without the production of virions. In the absence of viral production, at steady state, the distribution of virions by the number of sites bound is given by a binomial distribution, with the proportion being a simple function of antibody affinity (Kon/Koff) and concentration; this generalizes to a multinomial distribution in the case of two or more kinds of antibodies. In the presence of viral production, the role of affinity is replaced by an infection analog of affinity (IAA), with IAA=Kon/(Koff+dv+r), where dv is the virus decaying rate and r is the infection growth rate. Because in vivo dv can be large, the amount of binding as well as the effect of Koff on binding are substantially reduced. When neutralization is added, the effect of Koff is similarly small which may help explain the relatively high Koff reported for many antibodies. We next show that the n+2-dimensional model used for neutralization can be simplified to a 2-dimensional model. This provides some justification for the simple models that have been used in practice. A corollary of our results is that an unexpectedly large effect of Koff in vivo may point to mechanisms of neutralization beyond stoichiometry. Our results suggest reporting Kon and Koff separately, rather than focusing on affinity, until the situation is better resolved both experimentally and theoretically.

Many vaccines against respiratory viruses have proven suboptimal in generating long-lasting sterilizing immunity and preventing transmission among populations. It is well established that respiratory tract resident memory CD8 T cells (TRM) induced by vaccination can reduce viral burdens and limit immunopathology upon direct inoculation of respiratory viruses. However, the ability of respiratory tract CD8 TRM to limit viral transmission has remained elusive. We developed a murine model to investigate the role of respiratory tract CD8 TRM in viral transmission using Sendai virus, which naturally transmits among mice. Contact mice were first immunized to generate Sendai virus-specific CD8 TRM and challenged by co-housing with a Sendai virus-infected index mouse. We demonstrated that CD8 TRM can limit viral transmission and decrease viral burdens, even in the absence of B cell responses, CD4 T cells, and circulating effector memory T cells. We evaluated multiple CD8 T cell effector mechanisms for their importance in limiting viral transmission and determined that IFN-γ secretion was critical. Upon IFN-γ signaling, nasal cavity epithelial cells adopted an anti-viral program. Furthermore, CD8 TRM in the nasal cavity alone were sufficient to limit respiratory virus transmission. These findings suggest that respiratory tract CD8 TRM, particularly those within the upper respiratory tract, are a promising vaccine target to prevent respiratory virus transmission among populations.

Many emerging and reemerging pathogens originate from wildlife, but nearly all wild species are unreachable using conventional vaccination, which requires capture of and vaccine administration to individual animals. By enabling immunization at scales sufficient to interrupt pathogen transmission, transmissible vaccines (TVs) that spread themselves through wildlife populations by infectious processes could potentially transform the management of otherwise intractable challenges to public health, wildlife conservation, and animal welfare. However, generating TVs likely requires modifying viruses that would be intended to spread in nature, which raises concerns ranging from technical feasibility, to safety and security risks, to regulatory uncertainties (1, 2). We propose a series of commitments and strategies for vaccine development—beginning with a priori decisions on vaccine design and continuing through to stakeholder codevelopment [see supplementary materials (SM)]—that we believe increase the likelihood that the potential risks of vaccine transmission are outweighed by benefits to conservation, animal welfare, and zoonosis prevention.

Introduction Transmissible vaccines offer a novel approach to suppressing viruses in wildlife populations, with possible applications against viruses that infect humans as zoonoses – Lassa, Ebola, rabies. To ensure safety, current designs propose a recombinant vector platform in which the vector is isolated from the target wildlife population. Because using an endemic vector creates the potential for preexisting immunity to block vaccine transmission, these designs focus on vector viruses capable of superinfection, spreading throughout the host population following vaccination of few individuals. Areas covered We present original theoretical arguments that, regardless of its R0 value, a recombinant vaccine using a superinfecting vector is not expected to expand its active infection coverage when released into a wildlife population that already carries the vector. However, if superinfection occurs at a high rate such that individuals are repeatedly infected throughout their lives, the immunity footprint in the population can be high despite a low incidence of active vaccine infections. Yet we provide reasons that the above expectation is optimistic. Expert Opinion High vaccine coverage will typically require repeated releases or release into a population lacking the vector, but careful attention to vector choice and vaccine engineering should also help improve transmissible vaccine utility.