Mark K Slifka

Oregon Health & Science University | OHSU · Neuroscience

Yellow fever virus (YFV) is endemic in >40 countries and causes viscerotropic disease with up to 20%–60% mortality. Successful live-attenuated yellow fever (YF) vaccines were developed in the mid-1930s, but their use is restricted or formally contraindicated in vulnerable populations including infants, the elderly, and people with compromised immun...

Background: Vaccination is typically administered without regard to site of prior vaccination but this factor may substantially impact downstream immune responses. Methods: We assessed serological responses to initial COVID-19 vaccination in baseline seronegative adults who received second-dose boosters in the ipsilateral or contralateral arm re...

Diarrheal diseases remain one of the leading causes of death for children under 5 globally, disproportionately impacting those living in low- and middle-income countries (LMIC). Campylobacter spp., a zoonotic pathogen, is one of the leading causes of food-borne infection in humans. Yet to be cultured Campylobacter spp. contribute to the total burde...

In 2022 the World Health Organization declared a Public Health Emergency for an outbreak of mpox, the zoonotic Orthopoxvirus (OPV) affecting at least 104 nonendemic locations worldwide. Serologic detection of mpox infection is problematic, however, due to considerable antigenic and serologic cross‐reactivity among OPVs and smallpox‐vaccinated indiv...

The burden of cervical cancer is disproportionately distributed globally, with the vast majority of cases occurring in low- and middle-income countries. Women with human immunodeficiency virus (HIV) (WWH) are at increased risk of human papillomavirus (HPV) infection and cervical cancer as compared to HIV-negative individuals. HPV vaccination remain...

Campylobacter-associated enteric disease is estimated to be responsible for more than 160 million cases of gastroenteritis each year and is linked to growth stunting of infants living under conditions of poor sanitation and hygiene. Here, we examine naturally occurring Campylobacter-associated diarrhea among rhesus macaques as a model to determine...

Diarrheal diseases remain one of the leading causes of death for children under 5 globally, disproportionately impacting those living in low- and middle-income countries (LMIC). Campylobacter spp . is a zoonotic pathogen found in many animal species and is one of the leading causes of food-borne infection in humans, and yet to be cultured Campyloba...

The World Health Organization has declared a Public Health Emergency for an ongoing mpox (formerly monkeypox) outbreak, due to multiple cases of mpox in regions of the world in which infections have not been previously seen. The outbreak is notable for the high degree of human-human transmissions spreading primarily through sexual contacts. Current...

In 2022 the World Health Organization declared a Public Health Emergency for an outbreak of mpox, the zoonotic Orthopoxvirus (OPV) affecting at least 103 non-endemic locations world-wide. Serologic detection of mpox infection is problematic, however, due to considerable antigenic and serologic cross-reactivity among OPVs and smallpox-vaccinated ind...

Yellow fever virus (YFV) is a reemerging global health threat, driven by several factors, including increased spread of the mosquito vector and rapid urbanization. Although a prophylactic vaccine exists, vaccine hesitancy, supply deficits, and distribution difficulties leave specific populations at risk of severe YFV disease, as evidenced by recent...

The genome of cowpoxvirus (CPXV) could be considered prototypical for orthopoxviridae (OXPV) since it contains many open reading frames (ORFs) absent or lost in other OPXV, including vaccinia virus (VACV). These additional ORFs are non-essential for growth in vitro but are expected to contribute to the broad host range, virulence and immune evasion...

Diphtheria is rare in the United States. and many industrialized nations due to development of an effective vaccine, coupled with high vaccination coverage. Although there is continued risk of importation and transmission of Corynebacterium diphtheriae, C. ulcerans has now become the dominant source of diphtheria cases among several European countr...

Pregnancy and the postpartum period result in some of the most dramatic metabolic, hormonal, and physiological changes that can be experienced by an otherwise healthy adult. The timing and magnitude of these changes is key for both maternal and fetal health. One of the factors believed to critically modulate these physiological changes is the mater...

Chikungunya virus (CHIKV) is an emerging/re-emerging mosquito-borne pathogen responsible for explosive epidemics of febrile illness characterized by debilitating polyarthralgia and the risk of lethal infection among the most severe cases. Despite the public health risk posed by CHIKV, no vaccine is currently available. Using a site-directed hydroge...

Age-related changes in the immune system increase susceptibility to infectious diseases. Vaccines are an important tool to prevent infection or boost immunological memory; however, vaccines are less effective in aged individuals. In order to protect our aging population from the threat of infectious diseases, we must gain a better understanding of...

Few countermeasures to treat Yellow Fever virus (YFV) infection are under development, because vaccines have helped to limit new infections. Unfortunately, vaccine hesitancy, supply deficits, and a paucity of therapeutic options have left individuals at risk. Here, we tested potent YFV-specific neutralizing monoclonal antibodies in rodents and non-...

Pregnancy and the postpartum period result in some of the most dramatic metabolic, hormonal, and physiological changes that can be experienced by an otherwise healthy adult. The timing and magnitude of these changes is key for both maternal and fetal health. One of the factors believed to critically modulate these physiological changes is the mater...

Background Life-threatening viral diseases such as eczema herpeticum (EH) and eczema vaccinatum (EV) occur in less than 5% of individuals with atopic dermatitis (AD). The diagnosis of AD, however, excludes all individuals with AD from smallpox vaccination. Objective To identify circulatory and skin lipid biomarkers associated with EH and EV. Meth...

Individuals with chronic lymphocytic leukemia (CLL) have significant immune disfunction, often further disrupted by treatment. While currently available COVID-19 vaccinations are highly effective in immunocompetent individuals, they are often poorly immunogenic in CLL patients. It is important to understand the role a heterologous boost would have...

Environmental enteric dysfunction is associated with malnutrition as well as infant growth stunting and has been classically defined by villous blunting, decreased crypt-to-villus ratio, and inflammation in the small intestine. Here, we characterized environmental enteric dysfunction among infant rhesus macaques that are naturally exposed to enteri...

The unprecedented SARS-CoV-2 pandemic has called for substantial investigations into the capacity of the human immune system to protect against reinfection and keep pace with the evolution SARS-CoV-2. We evaluated the magnitude and durability of the SARS-CoV-2 specific antibody responses against parental WA1 SARS-CoV-2 receptor binding domain (RBD)...

Chronic Lymphocytic Leukemia (CLL) is predominantly a B-lymphocyte leukemia associated with immune defects that are often exacerbated by CLL directed therapies. SARS-CoV-2 infection poses a significant risk of illness or mortality to CLL patients, and while SARS-CoV-2 vaccines are highly effective in immunocompetent individuals, efficacy varies sub...

Importance: Individuals with Chronic Lymphocytic Leukemia have significant immune disfunction, often further disrupted by treatment. While currently available COVID-19 vaccinations are highly effective in immunocompetent individuals, they are often poorly immunogenic in CLL patients. It is important to understand the role heterologous boost would h...

Background: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. Objective: By leveraging data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, the Consortium on Asthma among African-ancestry Pop...

Despite the impact of childhood diarrhea on morbidity and mortality, our understanding of its sequelae has been significantly hampered by the lack of studies that examine samples across the entire intestinal tract. Infant rhesus macaques are naturally susceptible to human enteric pathogens and recapitulate the hallmarks of diarrheal disease such as...

In this investigation we examined the magnitude, breadth, and durability of SARS-CoV-2 specific antibodies in two distinct B-cell compartments: long-lived plasma cell-derived antibodies in the plasma, and peripheral memory B-cells along with their associated antibody profiles elicited after in vitro stimulation. We found that magnitude varied among...

Background While numerous genetic loci associated atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited. Objective This study aims to determine if polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful pred...

The COVID-19 pandemic is a global health emergency, and the development of a successful vaccine will ultimately be required to prevent the continued spread and seasonal recurrence of this disease within the human population. However, very little is known about either the quality of the adaptive immune response or the viral Ag targets that will be n...

The vaginal microbiota plays an important role in women’s reproductive and urogenital health. It is now well accepted that a “healthy” vaginal microbiome is dominated by Lactobacillus species. Disturbances in this microbial community can lead to several adverse outcomes, including pelvic inflammatory disease and bacterial vaginosis (BV), as well as...

Background Serological confirmation of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for understanding the dynamics of the pandemic and determining seroprevalence rates within afflicted communities. Common challenges with SARS-CoV-2 serological assays include poor analytical s...

The vaginal microbiota plays an important role in women’s reproductive and urogenital health. Disturbances in this microbial community can lead to several adverse outcomes including pelvic inflammatory disease, bacterial vaginosis (BV) as well as increased susceptibility to sexually transmitted infections, miscarriage, and pre-term births. It is no...

Significance Fatal cases of yellow fever are preceded by the development of hemorrhagic complications. While yellow fever virus is known to infect hepatocytes, the relationship between hepatocyte infection and the development of hemorrhage is currently undefined. Here, we identified high concentrations of D-dimer in the blood of yellow fever patien...

Campylobacter coli and Campylobacter jejuni are responsible for 400 million to 500 million cases of enteric disease each year and represent the most common cause of bacterial gastroenteritis worldwide. Despite its global importance, Campylobacter vaccine development has been hampered by the lack of animal models that recapitulate human disease path...

Background: The World Health Organization (WHO) does not recommend routine adult booster vaccination for tetanus and diphtheria after completion of the childhood vaccination series. However, many countries continue to implement adult booster vaccinations, leading to the question of whether this is necessary to reduce the incidence of these 2 rare...

Allogeneic hematopoietic stem cell transplantation (HSCT) and xenotransplantation are accompanied by viral reactivations and virus‐associated complications resulting from immune deficiency. Here, in a Mauritian cynomolgus macaque model of fully MHC‐matched allogeneic HSCT, we report reactivations of cynomolgus polyomavirus, lymphocryptovirus, and c...

Background: It is unclear if HIV infection results in permanent loss of T cell memory or if it impacts pre-existing antibodies to childhood vaccinations/infections. Methods: We conducted a matched cohort study involving 50 pairs of HIV+ and HIV- women. Total memory T cell responses were measured after anti-CD3 stimulation or after vaccinia virus...

Background: The once-in-a-lifetime recommendation for vaccination against yellow fever virus (YFV) has been controversial, leading to increased scrutiny of the durability of immunity after 17D vaccination. Methods: This is a cross-sectional analysis of 17D vaccinees living in nonendemic Portland, Oregon. Neutralization assays were used to determ...

Background: Diarrhea is the second leading cause of death in children under 5 years of age. Enhanced understanding of causal pathways, pathogenesis, and sequelae of diarrhea is urgently needed. Although the gut microbiota is believed to play a role in susceptibility to diarrheal diseases, our understanding of this association remains incomplete. I...

Background: West Nile virus (WNV) is the most common mosquito-borne infection in the United States. HydroVax-001 WNV is a hydrogen peroxide inactivated, whole virion (WNV-Kunjin strain) vaccine adjuvanted with aluminum hydroxide. Methods: We performed a phase 1, randomized, placebo-controlled, double-blind (within dosing group), dose escalation...

Vaccines play a vital role in protecting our communities against infectious disease. Unfortunately, some vaccines provide only partial protection or in some cases vaccine-mediated immunity may wane rapidly, resulting in either increased susceptibility to that disease or a requirement for more booster vaccinations in order to maintain immunity above...

Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted alphavirus with a high case mortality rate in humans. EEEV is a biodefence concern because of its potential for aerosol spread and the lack of existing countermeasures. Here, we identify a panel of 18 neutralizing murine monoclonal antibodies (mAbs) against the EEEV E2 glycoprotein,...

West Nile virus (WNV) is the most frequent mosquito-borne disease reported in the continental United States and although an effective veterinary vaccine exists for horses, there is still no commercial vaccine approved for human use. We have previously tested a 3% hydrogen peroxide (H2O2)-based WNV inactivation approach termed, HydroVax, in Phase I...

Determining the duration of protective immunity requires quantifying the magnitude and rate of loss of antibodies to different virus and vaccine antigens. A key complication is heterogeneity in both the magnitude and decay rate of responses of different individuals to a given vaccine, as well as of a given individual to different vaccines. We analy...

Plots of the relative magnitude (panel A) and decay rates (panel B) of responses in different individuals. The relative magnitude of the response of each individual to a given vaccine or virus antigen is determined by comparing it to the average magnitude of the response to that vaccine or virus antigen and similarly for decay rate. Specifically, w...

Summary table for the responses to different vaccine and virus antigens. We show the average magnitude and decay rates of responses to the different vaccines and the extent of variation in these quantities. Because we do not have values for the protective titer for mumps and VZV, the mean magnitude of these cannot be compared to the responses to th...

The data for the Figs 2, 3, 4, 5, S1, S2 and S3 are in the relevant sheets of S1 Data. (XLSX)

The R scripts used for the analysis of the data. These R scripts explain how to import the data from S1_data.xlsx file supplied and generate all the figures and tables in the paper. The PDF document contains both the scripts and shows the output for all the figures and tables in the manuscript generated by these scripts. (PDF)

Summary table with AIC values showing that random effects due to the vaccine, the individual, and their interaction account for most of the variation in responses of different individuals to different pathogens. The SD indicates the amount of variation in the relevant random effect, and r indicates the correlation between the variation in magnitude...

Shows all curated data used in analysis. The dotted lines indicate the threshold of protection. The y-axis is the log10 (ELISA titer). The boxplot at the bottom right indicates the number of points per individual response to each vaccine or virus antigen. The asterisk for mumps and VZV indicates the absence of a defined threshold for protection. Un...

Correlation between the magnitude and decay rate of responses to vaccines. We plot the magnitude versus decay rate of each individual's response variation for each vaccine or virus antigen. We show the linear regression line and 95% pointwise CI for that line. While there appears to be a trend for higher-responding individuals to have lower rate of...

Vaccines are considered one of the most important advances in modern medicine and have greatly improved our quality of life by reducing or eliminating many serious infectious diseases. Successful vaccines have been developed against many of the most common human pathogens, and this success has not been dependent upon any one specific class of vacci...

Pre-existing serum antibodies play an important role in vaccine-mediated protection against infection but the underlying mechanisms of immune memory are unclear. Clinical studies indicate that antigen-specific antibody responses can be maintained for many years, leading to theories that reactivation/differentiation of memory B cells into plasma cel...

Lymphatic vessels lie at the interface between peripheral sites of pathogen entry, adaptive immunity, and the systemic host. Though the paradigm is that their open structure allows for passive flow of infectious particles from peripheral tissues to lymphoid organs, virus applied to skin by scarification does not spread to draining lymph nodes. Usin...

Humoral immunity is critical for viral control, but the identity and mechanisms regulating human antiviral B cells are unclear. Here, we characterized human B cells expressing T-bet and analyzed their dynamics during viral infections. T-bet+ B cells demonstrated an activated phenotype, a distinct transcriptional profile, and were enriched for expre...

West Nile virus (WNV) is a mosquito-transmitted pathogen with a wide geographical range that can lead to long-term disability and death in some cases. Despite the public health risk posed by WNV, including an estimated 3 million infections in the United States alone, no vaccine is available for use in humans. Here, we present a scaled manufacturing...

Monkeypox (MPXV) and cowpox (CPXV) are emerging agents that cause severe human infections on an intermittent basis, and variola virus (VARV) has potential for use as an agent of bioterror. Vaccinia immune globulin (VIG) has been used therapeutically to treat severe orthopoxvirus infections but is in short supply. We generated a large panel of ortho...

Author Previous studies have demonstrated that HIV-specific CD8⁺ T cells are critical for the initial control of HIV infection. However, this control is typically incomplete, being able to neither clear infection nor maintain plasma viremia below undetectable levels. Mounting evidence has implicated CD8⁺ T cell cytotoxic capacity as a critical com...

Introduction: The World Health Organization (WHO) and other health agencies have concluded that yellow fever booster vaccination is unnecessary since a single dose of vaccine confers lifelong immunity. Areas covered: We reviewed the clinical studies cited by health authorities in their investigation of both the safety profile and duration of imm...

Chronic hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic effects, including central nervous system (CNS) damage and neuropsychiatric impairments. Alcohol abuse can exacerbate these adverse effects on brain and behavior, but the molecular mechanisms are not well understood. This st...

B cells play a central role in antibody-mediated rejection and certain autoimmune diseases. However, B cell-targeted therapy such as anti-CD20 B cell-depleting antibody (aCD20) has yielded mixed results in improving outcomes. In this study, we investigated whether an accelerated B cell reconstitution leading to aCD20 depletion resistance could acco...

Background. Many adult immunization schedules recommend that tetanus and diphtheria vaccination be performed every 10 years. In light of current epidemiological trends of disease incidence and rates of vaccine-associated adverse events, the 10-year revaccination schedule has come into question. Methods. We performed cross-sectional analysis of seru...

Vaccines play a vital role in public health and arguably represent the most important advance in modern medicine. Most successful vaccines have been developed empirically but in order to expedite future vaccine development, a better understanding of the tenets of successful vaccine- mediated protection and long-term immunity is needed. The overridi...

Animal models that provide new insights into the neuroimmunological mechanisms affected by co-morbid alcohol dependence and chronic viral infection are needed. Our recent pilot study of adults with HCV (n = 10) found that tumor necrosis factor-alpha and monocyte chemoattractant protein-1 levels were higher in adults who reported more hazardous drin...

Antibody responses to viral infections are sustained for decades by long-lived plasma cells (LLPCs). However, LLPCs have yet to be characterized in humans. Here we used CD19, CD38, and CD138 to identify four PC subsets in human bone marrow (BM). We found that the CD19(-)CD38(hi)CD138(+) subset was morphologically distinct, differentially expressed...

Natural killer (NK) cells provide a first line of defense against infection via the production of antiviral cytokines and direct lysis of target cells. Cytokines such as interleukin 12 (IL-12) and IL-18 are critical regulators of NK cell activation, but much remains to be learned about how cytokines interact to regulate NK cell function. Here, we h...

Immunization with vaccinia virus (VACV) induces cross-protective immunity to variola, the causative agent of smallpox, and other clinically important poxviral species, such as cowpox and monkeypox viruses. Vaccine-mediated protection has been correlated with elicitation of broad neutralizing antibodies (Abs). However, the specificity and breadth of...

Cytomegalovirus accelerates transplant vascular sclerosis (TVS) and chronic rejection (CR) in solid organ transplants; however, the mechanisms involved are unclear. We determined the efficacy of a CMV vaccine in preventing CMV-accelerated rat cardiac allograft rejection in naïve recipients of CMV+ donor hearts. F344 donor rats were infected with RC...

Infection with yellow fever virus (YFV), an explosively replicating flavivirus, results in viral hemorrhagic disease characterized by cardiovascular shock and multi-organ failure. Unvaccinated populations experience 20 to 50% fatality. Few studies have examined the pathophysiological changes that occur in humans during YFV infection due to the spor...

Virus-specific CD8(+) T cells provide classical adaptive immunity by responding to cognate peptide antigen, but they may also act in an "innate" capacity by responding directly to cytokine stimulation. Here, we examined regulation of these distinct T cell functions by anti-inflammatory cytokines (IL-4, IL-10, TGFβ). Innate IFNγ production by CD8(+)...

It is estimated that over 2.5 billion people are at risk for contracting dengue, a virus responsible for 50–390 million infections in addition to thousands of hospitalizations and deaths each year. There are no licensed vaccines available to combat this pathogen but substantial efforts are underway to develop live-attenuated, inactivated, and subun...