Divergent antibody recognition profiles are generated by protective mRNA vaccines against Marburg and Ravn viruses. (preprint)

The first-ever recent Marburg virus (MARV) outbreak in Ghana, West Africa and Equatorial Guinea has refocused efforts towards the development of therapeutics since no vaccine or treatment has been approved. mRNA vaccines were proven successful in a pandemic-response to severe acute respiratory syndrome coronavirus-2, making it an appealing vaccine platform to target highly pathogenic emerging viruses. Here, 1-methyl-pseudouridine-modified mRNA vaccines formulated in lipid nanoparticles (LNP) were developed against MARV and the closely-related Ravn virus (RAVV), which were based on sequences of the glycoproteins (GP) of the two viruses. Vaccination of guinea pigs with both vaccines elicited robust binding and neutralizing antibodies and conferred complete protection against virus replication, disease and death. The study characterized antibody responses to identify disparities in the binding and functional profiles between the two viruses and regions in GP that are broadly reactive. For the first time, the glycan cap is highlighted as an immunoreactive site for marburgviruses, inducing both binding and neutralizing antibody responses that are dependent on the virus. Profiling the antibody responses against the two viruses provided an insight into how antigenic differences may affect the response towards conserved GP regions which would otherwise be predicted to be cross-reactive and has implications for the future design of broadly protective vaccines. The results support the use of mRNA-LNPs against pathogens of high consequence.

Intranasal mRNA-LNP vaccination protects hamsters from SARS-CoV-2 infection (preprint)

Intranasal vaccination represents a promising approach for preventing disease caused by respiratory pathogens by eliciting a mucosal immune response in the respiratory tract that may act as an early barrier to infection and transmission. This study investigated immunogenicity and protective efficacy of intranasally administered messenger RNA (mRNA)-lipid nanoparticle (LNP) encapsulated vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Syrian golden hamsters. Intranasal mRNA-LNP vaccination systemically induced spike-specific binding (IgG and IgA) and neutralizing antibodies with similar robustness to intramuscular controls. Additionally, intranasal vaccination decreased viral loads in the respiratory tract, reduced lung pathology, and prevented weight loss after SARS-CoV-2 challenge. This is the first study to demonstrate successful immunogenicity and protection against respiratory viral infection by an intranasally administered mRNA-LNP vaccine.

Reports of the Death of Expertise May Be Exaggerated: Limits on Knowledge Resistance in Health and Medicine (preprint)

During the past decade the idea that expertise is dead, or at best moribund, has become commonplace. Knowledge resistance appears to be growing more politicized and is increasing across a wide range of science-based topics, such as agriculture, evolution and genetics, vaccination, and climate change; even flat-earth beliefs are undergoing a renaissance. But in many of these areas, denying expert authority is cost-free in everyday behavior, making it more rational for people to prize identity and group affiliation over realism. To probe the health of expertise in a domain with everyday consequences for knowledge resistance, we conducted three incentive-compatible studies of laypeople’s preferences for sources of information they would read about specific medical conditions (e.g., heart disease, cancer, COVID-19). We found quite rational preference patterns, by which people preferred sources based on experts (physicians and scientists) over non-experts (celebrities and politicians) and group consensus (professional societies, polls) over individual opinions. These findings held most strongly for issues of personal medical concern, but were robust for less concerning health conditions, and for the highly politicized topic of COVID-19. Individuals who scored higher in intellectual humility and preferences for rational over experiential thinking were more likely to prefer the most expert sources. Expertise retains broad respect in the medical domain, at least when one’s own health is at stake.

Automated, miniaturized, and scalable screening of healthcare workers, first responders, and students for SARS-CoV-2 in San Diego County (preprint)

Background: Successful containment strategies for SARS-CoV-2, the causative virus of the COVID-19 pandemic, have involved widespread population testing that identifies infections early and enables rapid contact tracing. In this study, we developed a rapid and inexpensive RT-qPCR testing pipeline for population-level SARS-CoV-2 detection, and used this pipeline to establish a clinical laboratory dedicated to COVID-19 testing at the University of California San Diego (UCSD) with a processing capacity of 6,000 samples per day and next-day result turnaround times. Methods and findings: Using this pipeline, we screened 6,786 healthcare workers and first responders, and 21,220 students, faculty, and staff from UCSD. Additionally, we screened 6,031 preschool-grade 12 students and staff from public and private schools across San Diego County that remained fully or partially open for in-person teaching during the pandemic. Between April 17, 2020 and February 5, 2021, participants provided 161,582 nasal swabs that were tested for the presence of SARS-CoV-2. Overall, 752 positive tests were obtained, yielding a test positivity rate of 0.47%. While the presence of symptoms was significantly correlated with higher viral load, most of the COVID-19 positive participants who participated in symptom surveys were asymptomatic at the time of testing. The positivity rate among preschool-grade 12 schools that remained open for in-person teaching was similar to the positivity rate at UCSD and lower than that of San Diego County, with the children in private schools being less likely to test positive than the adults at these schools. Conclusions: Most schools across the United States have been closed for in-person learning for much of the 2020-2021 school year, and their safe reopening is a national priority. However, as there are no vaccines against SARS-CoV-2 currently available to the majority of school-aged children, the traditional strategies of mandatory masking, physical distancing, and repeated viral testing of students and staff remain key components of risk mitigation in these settings. The data presented here suggest that the safety measures and repeated testing actions taken by participating healthcare and educational facilities were effective in preventing outbreaks, and that a similar combination of risk-mitigation strategies and repeated testing may be successfully adopted by other healthcare and educational systems.

Informing patients that they are at high risk for serious complications of viral infection increases vaccination rates (preprint)

For many vaccine-preventable diseases like influenza, vaccination rates are lower than optimal to achieve community protection. Those at high risk for infection and serious complications are especially advised to be vaccinated to protect themselves. Using influenza as a model, we studied one method of increasing vaccine uptake: informing high-risk patients, identified by a machine learning model, about their risk status. Patients (N=39,717) were evenly randomized to (1) a control condition (exposure only to standard direct mail or patient portal vaccine promotion efforts) or to be told via direct mail, patient portal, and/or SMS that they were (2) at high risk for influenza and its complications if not vaccinated; (3) at high risk according to a review of their medical records; or (4) at high risk according to a computer algorithm analysis of their medical records. Patients in the three treatment conditions were 5.7% more likely to get vaccinated during the 112 days post-intervention (p < .001), and did so 1.4 days earlier (p < .001), on average, than those in the control group. There were no significant differences among risk messages, suggesting that patients are neither especially averse to nor uniquely appreciative of learning their records had been reviewed or that computer algorithms were involved. Similar approaches should be considered for COVID-19 vaccination campaigns.

A Mega-Study of Text-Message Nudges Encouraging Patients to Get Vaccinated at their Pharmacy (preprint)

We partnered with Walmart to test 22 nudges designed to boost vaccination rates in their pharmacies. Nudges were delivered via text message to over 650,000 Walmart pharmacy patients in the fall of 2020 and encouraged patients to visit Walmart for a flu vaccine. We demonstrate that behaviorally informed messages increase pharmacy vaccination rates by an average of 6.7% over a roughly three-month follow-up period. The most effective messages in our field experiment matched the tone of typical pharmacy communications and reminded patients that a flu shot was waiting for them. These insights suggest that carefully crafted messages informed by the results of this study could nudge the adoption of other vaccines for other infectious diseases, including COVID-19.

A Mega-Study of Text-Based Nudges Encouraging Patients to Get Vaccinated at an Upcoming Doctor’s Appointment (preprint)

Many Americans fail to get life-saving vaccines each year, and the availability of a vaccine for COVID-19 makes the challenge of encouraging vaccination more urgent than ever. We present a large field experiment (N=47,306) testing 19 nudges delivered to patients via text message and designed to boost adoption of the influenza vaccine. Our findings suggest that text messages sent prior to a primary care visit can boost vaccination rates by an average of 5%. Overall, interventions performed better when they were (a) framed as reminders to get flu shots that were already reserved for the patient and (b) congruent with the sort of communications patients expected to receive from their healthcare provider (i.e., not surprising, casual, or interactive). The best-performing intervention in our study reminded patients twice to get their flu shot at their upcoming doctor’s appointment and indicated it was reserved for them. This successful script could be used as a template for campaigns to encourage the adoption of life-saving vaccines, including against COVID-19.

mRNA-1273 efficacy in a severe COVID-19 model: attenuated activation of pulmonary immune cells after challenge (preprint)

ABSTRACT The mRNA-1273 vaccine was recently determined to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from interim Phase 3 results. Human studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibit more severe SARS-CoV-2 disease similar to hospitalized patients, making them pertinent for vaccine evaluation. We demonstrate that prime or prime-boost administration of mRNA-1273 in hamsters elicited robust neutralizing antibodies, ameliorated weight loss, suppressed SARS-CoV-2 replication in the airways, and better protected against disease at the highest prime-boost dose. Unlike in mice and non-human primates, mRNA-1273- mediated immunity was non-sterilizing and coincided with an anamnestic response. Single-cell RNA sequencing of lung tissue permitted high resolution analysis which is not possible in vaccinated humans. mRNA-1273 prevented inflammatory cell infiltration and the reduction of lymphocyte proportions, but enabled antiviral responses conducive to lung homeostasis. Surprisingly, infection triggered transcriptome programs in some types of immune cells from vaccinated hamsters that were shared, albeit attenuated, with mock-vaccinated hamsters. Our results support the use of mRNA-1273 in a two-dose schedule and provides insight into the potential responses within the lungs of vaccinated humans who are exposed to SARS-CoV-2.

Healthcare worker intentions to receive a COVID-19 vaccine and reasons for hesitancy: A survey of 16,158 health system employees on the eve of vaccine distribution (preprint)

Healthcare workers (HCWs) have been recommended to receive first priority for limited COVID-19 vaccines. They have also been identified as potential ambassadors of COVID-19 vaccine acceptance, helping to ensure that sufficient members of a hesitant public accept COVID-19 vaccines to achieve population immunity. Yet HCWs themselves have shown vaccine hesitancy in other contexts and the few prior surveys of U.S. HCW intentions to receive a COVID-19 vaccine report acceptance rates of only 28% to 34%. However, it is unknown whether HCW acceptance remains low following mid-November announcements of the efficacy of the first COVID-19 vaccines and the issuance of two emergency use authorizations (EUA) in December. We report the results of a December 2020 survey ( N = 16,158; response rate 61%) administered by a large Pennsylvania health system to determine the intentions of its employees to receive a vaccine when it is offered to them. In a mixed sample of individuals serving in patient-facing and other roles, 55% would decide to receive a COVID-19 vaccine when offered, 16.4% would not, and 28.5% reported being undecided. The distribution of responses varied little across hospital campuses, between those in patient-facing roles and other HCWs, or by area or department of work. The higher rate of COVID-19 vaccine acceptance we observe may reflect the framing and timing of our survey. Among hesitant respondents, an overwhelming majority (90.3%) reported concerns about unknown risks and insufficient data. Other commonly reported concerns included known side effects (57.4%) and wanting to wait until they see how it goes with others (44.4%). We observed a substantial increase in self-reported intent to receive a COVID-19 vaccine after an FDA advisory committee voted to recommend an EUA. Among respondents who completed the survey after that point in time, 79% intend to receive a COVID-19 vaccine ( n = 1155). Although only suggestive, this trend offers hope that rates of COVID-19 vaccine acceptance may be higher among HCWs and, perhaps, the general public than more hypothetical survey results have indicated.

Healthcare worker intentions to receive a COVID-19 vaccine and reasons for hesitancy: A survey of 16,158 health system employees on the eve of vaccine distribution (preprint)

Now published in JAMA Network Open doi: 10.1001/jamanetworkopen.2021.5344. Healthcare workers (HCWs) have been recommended to receive first priority for limited COVID-19 vaccines. They have also been identified as potential ambassadors of COVID-19 vaccine acceptance, helping to ensure that sufficient members of a hesitant public accept COVID-19 vaccines to achieve population immunity. Yet HCWs themselves have shown vaccine hesitancy in other contexts and the few prior surveys of U.S. HCW intentions to receive a COVID-19 vaccine report acceptance rates of only 28% to 34%. However, it is unknown whether HCW acceptance remains low following mid-November announcements of the efficacy of the first COVID-19 vaccines and the issuance of two emergency use authorizations (EUA) in December. We report the results of a December 2020 survey (N = 16,158; response rate 61%) administered by a large Pennsylvania health system to determine the intentions of its employees to receive a vaccine when it is offered to them. In a mixed sample of individuals serving in patient-facing and other roles, 55% would decide to receive a COVID-19 vaccine when offered, 16.4% would not, and 28.5% reported being undecided. The distribution of responses varied little across hospital campuses, between those in patient-facing roles and other HCWs, or by area or department of work. The higher rate of COVID-19 vaccine acceptance we observe may reflect the framing and timing of our survey. Among hesitant respondents, an overwhelming majority (90.3%) reported concerns about unknown risks and insufficient data. Other commonly reported concerns included known side effects (57.4%) and wanting to wait until they see how it goes with others (44.4%). We observed a substantial increase in self-reported intent to receive a COVID-19 vaccine after an FDA advisory committee voted to recommend an EUA. Among respondents who completed the survey after that point in time, 79% intend to receive a COVID-19 vaccine (n = 1155). Although only suggestive, this trend offers hope that rates of COVID-19 vaccine acceptance may be higher among HCWs and, perhaps, the general public than more hypothetical survey results have indicated.