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Background Messenger RNA (mRNA)–1273 vaccine demonstrated 93.2% efficacy against coronavirus disease 2019 (COVID-19) in the Coronavirus Efficacy (COVE) trial. The humoral immunogenicity results are now reported. Methods Participants received 2 mRNA-1273 (100 µg) or placebo injections, 28 days apart. Immune responses were evaluated in a prespecified, randomly selected per-protocol immunogenicity population (n = 272 placebo; n = 1185 mRNA-1273). Serum binding antibodies (bAbs) and neutralizing antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–spike protein were assessed at days 1, 29, and 57 by baseline SARS-CoV-2–negative (n = 1197) and SARS-CoV-2–positive (n = 260) status, age, and sex. Results SARS-CoV-2–negative vaccinees had bAb geometric mean AU/mL levels of 35 753 at day 29 that increased to 316 448 at day 57 and nAb inhibitory dilution 50% titers of 55 at day 29 that rose to 1081 at day 57. In SARS-CoV-2–positive vacinees, the first mRNA-1273 injection elicited bAb and nAb levels that were 11-fold (410 049) and 27-fold (1479) higher than in SARS-CoV-2–negative vaccinees, respectively, and were comparable to levels after 2 injections in uninfected participants. Findings were generally consistent by age and sex. Conclusions mRNA-1273 elicited robust serologic immune responses across age, sex, and SARS-CoV-2 status, consistent with its high COVID-19 efficacy. Higher immune responses in those previously infected support a booster-type effect. Clinical Trials Registration. NCT04470427.

We performed a 2-year prospective cohort study to determine the incidence of dengue in Angoda, Colombo district, Sri Lanka (NCT02570152). The primary objective was to determine the incidence of acute febrile illness (AFI) because of laboratory confirmed dengue (LCD). Secondary objectives were to determine AFI incidence because of non-LCD, describe AFI symptoms, and estimate AFI incidence because of LCD by dengue virus (DENV)-type and age group. Participants from households with at least one minor and one adult (≤50 years) were enrolled and followed with scheduled weekly visits and, in case of AFI, unscheduled visits. Blood was collected for DENV detection at AFI visits, and symptoms recorded during the 7-day period following AFI onset. A total of 2,004 participants were enrolled (971 children, and 1,033 adults). A total of 55 LCD episodes were detected (overall incidence of 14.2 per 1,000 person-years). Incidence was the highest among children < 5 years (21.3 per 1,000 person-years) and 5–11 years (22.7 per 1,000 person-years), compared with adults ≥ 18 years (9.2 per 1,000 person-years). LCD was mostly (83.6%) caused by DENV-2 (n = 46), followed by DENV-1 (n = 6) and DENV-3 (n = 3). Common symptoms of LCD were headache, fatigue, myalgia, loss of appetite, and arthralgia. Incidence of AFI because of non-LCD was 47.3 per 1,000 person-years. In conclusion, this study reports the LCD incidence for a DENV-2 dominated epidemic that is comparable to the incidence of suspected dengue reported passively for 2017, one of the worst outbreaks in recent history.

Background Infectious mononucleosis (IM) is a contagious illness most frequently caused by Epstein-Barr virus (EBV). There are no recent published studies characterizing the burden of IM in the general US population over time. Methods Nationally representative samples of US ambulatory medical care data were utilized to estimate the N and proportion of visits with an IM diagnosis (based on ICD-9/10 codes) by time period. The National Ambulatory Medical Care Survey (NAMCS: 2006–2015) and National Hospital Ambulatory Care Survey (NHAMCS: 2006–2019) allow estimation of annual visits in free-standing and hospital-based ambulatory care, including emergency departments (EDs). Restricted cubic spline models were implemented to assess temporal trends. NHAMCS data were divided based on availability: combined outpatient and ED (2006–2011) and ED-only (2012–2019). Analyses were conducted using SAS 9.4 & SUDAAN 11.0.3. Results There were 3,182,082 IM-related visits in NAMCS, 599,837 in combined outpatient and ED NHAMCS, and 449,000 in ED-only NHAMCS across study years. For overlapping study years, 2006–2011, across all databases the average annual number of IM-related visits was 419,927. Persons aged 10–30 years comprised the majority of IM-related visits: 61% in NAMCS, 88% in combined NHAMCS, and 85% in ED-only NHAMCS. While 66% of IM visits were made by females in NAMCS, this proportion was lower in combined NHAMCS (58%) and ED-only NHAMCS (51%). Most IM-related visits were among non-Hispanic white patients: 92% in NAMCS, 87% in combined NHAMCS, and 67% in ED-only NHAMCS. Across databases and years, there were no consistent linear trends in IM-related visits (Figure 1). Rates of IM-related visits in NAMCS decreased from 4.18 (95% confidence interval [CI]: 3.02–5.78) in 2006–2009 to 2.89 (95% CI: 1.40–5.96) per 10,000 visits in 2013–2015; decreased from 4.94 (95% CI: 3.41, 7.16) in 2006–2007 to 3.56 (95% CI: 2.33–5.45) per 10,000 visits in 2010–2011 in combined NHAMCS data; and increased from 3.61 (95% CI: 2.30–5.67) in 2012–2014 to 5.98 (95% CI: 3.20–11.17) per 10,000 visits in 2018–2019 in ED-only data. Conclusion This study contributes epidemiologic information concerning IM and EBV by estimating US ambulatory medical care burden of IM over time and describing the demographics of those affected. Disclosures Christina Chandra, MPH, Moderna, Inc.: Contractor Jianheng Li, MBBS, MPH, Moderna, Inc.: Contractor W. Dana Flanders, MD, DSc, MPH, MA, Moderna, Inc.: Contractor Roderick McPhee, MD, PhD, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Robert Paris, MD, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Philip Buck, PhD, MPH, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Sumana Chandramouli, PhD, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Susan Hall, PhD, MS, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Cathy Lally, MSPH, Moderna, Inc.: Contractor.

BackgroundThis interim analysis of an ongoing phase I randomized clinical trial evaluated the safety, reactogenicity, and immunogenicity of mRNA-1283, a next-generation SARS-CoV-2 messenger RNA (mRNA)-based vaccine encoding 2 segments of the spike protein (ie, receptor binding and N-terminal domains).MethodsHealthy aged adults 18-55 years (n = 104) were randomized (1:1:1:1:1) to receive 2 doses of mRNA-1283 (10, 30, or 100 μg) or mRNA-1273 (100 μg) administered 28 days apart, or a single dose of mRNA-1283 (100 μg). Safety was assessed and immunogenicity was measured by serum neutralizing antibody (nAb) or binding antibody (bAb) responses.ResultsAt the interim analysis, no safety concerns were identified and no serious adverse events, adverse events of special interest, or deaths were reported. Solicited systemic adverse reactions were more frequent with higher dose levels of mRNA-1283 than with mRNA-1273. At day 57, all dose levels of the 2-dose mRNA-1283 regimen (including the lowest dose level [10 μg]) induced robust nAb and bAb responses that were comparable to those of mRNA-1273 (100 μg).ConclusionsmRNA-1283 was generally safe in adults, with all dose levels of the 2-dose regimen (10, 30, and 100 μg) eliciting similar immunogenicity as the 2-dose mRNA-1273 regimen (100 μg).Clinical Trials RegistrationClinicaltrials.gov,NCT04813796

The primary two-dose SARS-CoV-2 mRNA vaccine series are strongly immunogenic in humans, but the emergence of highly infectious variants necessitated additional doses of these vaccines and the development of new variant-derived ones1–4. SARS-CoV-2 booster immunizations in humans primarily recruit pre-existing memory B cells (MBCs)5–9. It remains unclear, however, whether the additional doses induce germinal centre (GC) reactions where reengaged B cells can further mature and whether variant-derived vaccines can elicit responses to novel epitopes specific to such variants. Here, we show that boosting with the original SARS- CoV-2 spike vaccine (mRNA-1273) or a B.1.351/B.1.617.2 (Beta/Delta) bivalent vaccine (mRNA-1273.213) induces robust spike-specific GC B cell responses in humans. The GC response persisted for at least eight weeks, leading to significantly more mutated antigen-specific MBC and bone marrow plasma cell compartments. Interrogation of MBC-derived spike-binding monoclonal antibodies (mAbs) isolated from individuals boosted with either mRNA-1273, mRNA-1273.213, or a monovalent Omicron BA.1-based vaccine (mRNA-1273.529) revealed a striking imprinting effect by the primary vaccination series, with all mAbs (n=769) recognizing the original SARS-CoV-2 spike protein. Nonetheless, using a more targeted approach, we isolated mAbs that recognized the spike protein of the SARS-CoV-2 Omicron (BA.1) but not the original SARS-CoV-2 spike from the mRNA-1273.529 boosted individuals. The latter mAbs were less mutated and recognized novel epitopes within the spike protein, suggesting a naïve B cell origin. Thus, SARS-CoV-2 boosting in humans induce robust GC B cell responses, and immunization with an antigenically distant spike can overcome the antigenic imprinting by the primary vaccination series.

The emergence of safe and effective mRNA platform-based COVID-19 vaccines from the recent pandemic has changed the face of vaccine development. Compared with conventional technologies used historically, mRNA-based vaccines offer a rapid flexible and robust approach to preventing disease caused by transient viral strains such as SAR2-CoV-2 variants of concern and seasonal influenza. Adaptations in the formulation of the mRNA delivery systems such as with lipid nanoparticle delivery (LNP) used in mRNA-1273 and BNT16b2b have enabled this technology to flourish under the urgent collective response and collaborative regulatory understanding derived from COVID-19 vaccine development. The application of mRNA-based therapeutics in other areas holds potential promise including combination vaccines that might deliver protections against multiple infectious diseases. Future studies and further advances in mRNA-based technologies will provide insight into the clinical efficacy and real-world effectiveness of vaccines as well as provisions with respect to the impact of reactogenicity profiles. Overall, the success of mRNA-based COVID-19 vaccines has helped unlock a platform likely to result in many more candidate vaccines entering clinical evaluation to address the unmet medical needs of other diseases including viral respiratory diseases, herpesviruses, and historically challenging vaccine targets such as HIV.

Sí, cuán "singular" es ese "Oriente" al que debemos hoy remitir al Perú con su "socialismo inca", su "modo de producción asiático" y su "despotismo oriental"! Pero sin duda se trata de ponernos de acuerdo y de convenir para empezar que lo más interesante en este Imperio "oriental" que fue el Perú inca —para nosotros por lo menos que vamos a ocuparnos aquí de cierto uso ideológico de este modelo de sociedad— no reside tanto en la presencia paradójica de una "clase dominante, asentada sobre todas las otras" o de lo que Louis Baudin llamó un poco rápidamente "socialismo de Estado", sino en ese "elemento ancestral" cuyos "orígenes se pierden en la prehistoria": El ayllu, la comunidad agrícola primitiva.

Four formulations of an investigational tetravalent dengue purified inactivated vaccine, administered as two doses one month (M) apart, were previously shown to be immunogenic and well-tolerated up to M13 of the phase I study NCT01702857. Here, we report results of the follow-up from M14 to year (Y) 3. One hundred healthy Puerto Rican adults, predominantly dengue virus (DENV)–primed, were randomized 1:1:1:1:1 to receive placebo or vaccine formulations: 1 μg/serotype/dose adjuvanted with aluminum, AS01E or AS03B, or aluminum-adjuvanted 4 μg/serotype/dose. No serious adverse events occurred. Two medically-attended potential immune-mediated disease cases, vaccination unrelated, were reported (groups 1 µg+Alum and 1 µg+AS03B). Of 14 instances of suspected dengue, none were laboratory confirmed. Geometric mean neutralizing antibody titers against DENV 1-4 waned from M14, but remained above pre-vaccination levels for DENV 1-3, with the highest values for group 1 µg+AS03B: 1220.1, 920.5, 819.4, and 940.5 (Y2), and 1329.3, 1169.2, 1219.8, and 718.9 (Y3). All formulations appeared to be safe and immunogenic during the 3-year follow-up.

Dengue disease and its causative agents, the dengue viruses (DENV-1–4), cause high morbidity in tropical and subtropical regions. We evaluated three dosing regimens of the investigational tetravalent AS03B-adjuvanted dengue-purified inactivated vaccine (DPIV+AS03B). In this phase 1/2, observer-blind, placebo-controlled study (NCT02421367), 140 healthy adults were randomized 1:1:2 to receive DPIV+AS03B according to the following regimens: 0–1 month (M), 0–1–6 M, or 0–3 M. Participants received DPIV+AS03B or placebo at M0, M1, M3, and M6 according to their dosing schedule. Primary objectives were 1) to evaluate the safety of DPIV+AS03B for 28 days (D) after each dose; 2) to demonstrate the added value of a booster dose (0–1–6 M versus 0–1 M) based on neutralizing antibody titers to each DENV type (DENV-1–4) at 28 D after the last dose; and, if this objective was met, 3) to demonstrate the benefit of a longer interval between the first and second doses (0–1 M versus 0–3 M). Adverse events (AEs) within 7 D after vaccination tended to be more frequent after DPIV+AS03B doses than placebo; the number of grade 3 AEs was low (≤ 4.5% after DPIV+AS03B; ≤ 2.9% after placebo), with no obvious differences across groups. Within 28 D following each dose, the frequency of unsolicited AEs after DPIV+AS03B appeared higher for three-dose (0–1–6 M) than two-dose (0–1 M and 0–3 M) regimens. No serious AEs were considered related to vaccination, and no potential immune-mediated diseases were reported during the study. All three schedules were well tolerated. Both primary immunogenicity objectives were demonstrated. The 0–3 M and 0–1–6 M regimens were more immunogenic than the 0–1 M regimen.

Background Although microscopy is a standard diagnostic tool for malaria and the gold standard, it is infrequently used because of unavailability of laboratory facilities and the absence of skilled readers in poor resource settings. Malaria rapid diagnostic tests (RDT) are currently used instead of or as an adjunct to microscopy. However, at very low parasitaemia (usually

What is the current landscape of audiobook publishing? Audiobooks, whose first organized venture in the form of recordings for the blind came at the same time as mass-market paperbacks, are now coming into their own as the fastest growing segment of trade publishing, after...

Many of us read books every day, either electronically or in print. We remember the books that shaped our ideas about the world as children, go back to favorite books year after year, give or lend books to loved ones and friends to share the stories we've loved especially, and discuss important books with fellow readers in book clubs and online communities. But for all the ways books influence us, teach us, challenge us, and connect us, many of us remain in the dark as to where they come from and how the mysterious world of publishing truly works. How are books created and how do they get to readers? The Book Business: What Everyone Needs to Know® introduces those outside the industry to the world of book publishing. Covering everything from the beginnings of modern book publishing early in the 20th century to the current concerns over the alleged death of print, digital reading, and the rise of Amazon, Mike Shatzkin and Robert Paris Riger provide a succinct and insightful survey of the industry in an easy-to-read question-and-answer format. The authors, veterans of "trade publishing," or the branch of the business that puts books in our hands through libraries or bookstores, answer questions from the basic to the cutting-edge, providing a guide for curious beginners and outsiders. How does book publishing actually work? What challenges is it facing today? How have social media changed the game of book marketing? What does the life cycle of a book look like in 2019? They focus on how practices are changing at a time of great flux in the industry, as digital creation and delivery are altering the commercial realities of the book business. This book will interest not only those with no experience in publishing looking to gain a foothold on the business, but also those working on the inside who crave a bird's eye view of publishing's evolving landscape. This is a moment of dizzyingly rapid change wrought by the emergence of digital publishing, data collection, e-books, audio books, and the rise of self-publishing; these forces make the inherently interesting business of publishing books all the more fascinating.

When were today’s major publishing houses founded? Although it was evolving, the trade book publishing business had remained largely the same for the first hundred years or so of the republic, until about a fifty-year period starting with the last quarter of the nineteenth...

What are agents and what do they do? Agents, also sometimes called “literary agents,” in the book business represent authors in their business interactions with publishers. The biggest publishers get nearly all their books through agents, so agents are effectively both scouts for new...

What are the various segments within the book business and how do they differ? The “book business” referred to in the title of this book is largely the trade book business in the United States. It seemed worth putting this segment of the overall...

Why is children’s book publishing so often viewed as a world apart from adult publishing? You can tell if someone doesn’t work in children’s publishing if she can’t tell you the difference between the Caldecott and Newbery Awards. The American Library Association (ALA) awards...

Although much of the e-book market and world is in flux, one thing is safe to say: the success of e-books is difficult for publishers and resellers to predict, and it has been from the beginning. If there is one thing the publishing establishment...

How do trade publishers make money? Take, as an almost absurd example of this business model, the companies that merged in 2013 to become Penguin Random House (PRH)—in 2016 they are said by Publishers Weekly to have had €3.7 billion in revenues,...

How has Amazon influenced publishing? Although Amazon began identifying itself as “earth’s biggest bookstore” and pretty much only sold books for the first few years of its existence, it has clearly outgrown its roots. Nevertheless, for obvious reasons given our focus in this book,...

What is the impact of nontraditional sales on the trade book industry? This book has focused on how traditional trade publishing operates today within the confines of the historical functions of publishing companies. We’ve addressed the growth of e-book publishing by trade publishers and...

BACKGROUND Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses. METHODS In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months. RESULTS A total of 26 of 30 subjects in the Fx017M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P < .0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P = .0009) were protected against infection, and protection differed between schedules (P = .040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge. DISCUSSIONS A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria. CLINICAL TRIALS REGISTRATION NCT01857869.

Background Prime-boost regimens comprising ALVAC-HIV (prime) and human immunodeficiency virus type 1 (HIV) Env (boost) induce HIV-specific neutralizing antibody and cell-mediated immune responses, but the impact of boost schedule and adjuvant requires further definition. Methods A phase 1 trial was conducted. In part A (open label), 19 volunteers received oligomeric glycoprotein 160 from HIV strains MN and LAI-2 (ogp160 MN/LAI-2) with dose escalation (25, 50, 100 μg) and either polyphosphazene (pP) or alum adjuvant. In part B, 72 volunteers received either placebo (n=12) or recombinant canarypox virus expressing HIV antigens (ALVAC-HIV [vCP205]) with different doses and schedules of ogp160 MN/LAI-2 in pP or alum (n = 60). Results The vaccines were safe and well tolerated, with no vaccine-related serious adverse events. Anti-gp70 V1V2 antibody responses were detected in 17 of 19 part A volunteers (89%) and 10%-100% of part B volunteers. Use of a peripheral blood mononuclear cell-based assay revealed that US-1 primary isolate neutralization was induced in 2 of 19 recipients of ogp160 protein alone (10.5%) and 5 of 49 prime-boost volunteers (10.2%). Among ogp160 recipients, those who received pP were more likely than those who received alum to have serum that neutralized tier 2 viruses (12% vs 0%; P = .015). Conclusions Administration of ogp160 with pP induces primary isolate tier 2 neutralizing antibody responses in a small percentage of volunteers, demonstrating proof of concept and underscoring the importance of further optimization of prime-boost strategies for HIV infection prevention. Clinical trials registration NCT00004579.

Leishmaniasis is a complex tropical disease caused by kinetoplastid parasitic protozoa of the genus Leishmania and is transmitted by the sand fly insect vector. Cutaneous leishmaniasis (CL) is the most common form of this disease, and CL infections often result in serious skin lesions and scars. CL remains a public health problem in many endemic countries worldwide because of the absence of effective, safe, and cost-effective drugs for treatment. One of the strategies we chose to use to find novel chemical entities worthy of further development as antileishmanials involved screening synthetic and natural products libraries. In our study, we developed a Leishmania major intracellular amastigote assay that uses the activity of luciferase as a measure of parasite proliferation and used this assay to screen a collection of 400 compounds obtained from Medicines for Malaria Venture (MMV) for their antileishmanial activity. Our results showed that 14 compounds identified by MMV as antimalarial drugs have antileishmanial activity and can potentially be optimized for CL drug development.

IntroductionInternal and external quality control (QC) of rapid diagnostic tests (RDTs) is important to increase reliability of RDTs currently used to diagnose malaria. However, cross-checking of used RDTs as part of quality assurance can rarely be done by off-site personnel because there is no guarantee of retaining visible test lines after manufacturers' recommended reading time. Therefore, this study examined the potential of using Fionet™ technology for remote RDT quality monitoring at seven clinics, identifying reasons for making RDT processing and interpretation errors, and taking corrective actions for improvement of diagnosis and consequently improved management of febrile patients.MethodsThe study was conducted at seven military health facilities in Mainland Tanzania and utilized RDTs capable of detecting Plasmodium falciparum specific Histidine-rich protein 2 (Pf-HRP2) and the genus specific Plasmodium lactate dehydrogenase (pLDH) for other species of plasmodium (P. vivax, P. malariae or P. ovale; pan-pLDH). Patients' data and images of processed RDTs from seven clinics were uploaded on a Fionet web portal and reviewed regularly to monitor preparation procedures and visual interpretation of test results compared to automated analysis using the Deki reader of RDT. Problems detected were rapidly communicated to remote laboratory personnel at the clinic for corrective action and follow-up of patients who were falsely diagnosed as negative and missed treatment. Factors contributing to making errors in visual interpretation of RDT results were analyzed during visits to the health facilities.ResultsA total of 1,367 (1.6%) out of 83,294 RDT test images uploaded to the Fionet portal had discordant test results of which 822 (60.1%) and 545 (39.9%) were falsely reported as negative and positive, respectively. False negative and false positive test results were common for a single test line in 515 (62.7%) and 741 (54.2%) tests, respectively. Out of 1,367 RDT images assessed, 98 (7.2%) had quality problems related to preparation procedures of which 95(96.9%) errors were due to putting too much blood on the sample well or insufficient buffer in the respective wells. The reasons for discrepant results included, false reporting of none existent lines in 526 (38.5%) tests, missing a faint positive line in 493 (36.1%), missing a strong positive line in 248(18.1%) and errors caused by poorly processed RDTs in 96 (7.2%) tests. Among the false negative tests (n = 822), 669 (48.9%) patients were eligible for follow-up and only 339 (48.5%) were reached and 291 (85.8%) received appropriate anti-malaria therapy.ConclusionFionet technology enabled remote monitoring of RDT quality issues, identifying reasons contributing to laboratory personnel making errors and provided a rapid method to implement corrective actions at remote sites to improve malaria diagnosis and consequently improved health care management of febrile patients infected with malaria.