Middle East Respiratory Syndrome Virus Research Articles

Engineering potent live attenuated coronavirus vaccines by targeted inactivation of the immune evasive viral deubiquitinase

Coronaviruses express a papain-like protease (PLpro) that is required for replicase polyprotein maturation and also serves as a deubiquitinating enzyme (DUB). In this study, using a Middle East respiratory syndrome virus (MERS-CoV) PLpro modified virus in which the DUB is selectively inactivated, we show that the PLpro DUB is an important MERS-CoV interferon antagonist and virulence factor. Although the DUB-negative rMERS-CoVMA replicates robustly in the lungs of human dipeptidyl peptidase 4 knock-in (hDPP4 KI) mice, it does not cause clinical symptoms. Interestingly, a single intranasal vaccination with DUB-negative rMERS-CoVMA induces strong and sustained neutralizing antibody responses and sterilizing immunity after a lethal wt virus challenge. The survival of naïve animals also significantly increases when sera from animals vaccinated with the DUB-negative rMERS-CoVMA are passively transferred, prior to receiving a lethal virus dose. These data demonstrate that DUB-negative coronaviruses could be the basis of effective modified live attenuated vaccines.

The Advances of Broad-Spectrum and Hot Anti-Coronavirus Drugs.

Coronaviruses, mainly including severe acute respiratory syndrome virus, severe acute respiratory syndrome coronavirus 2, Middle East respiratory syndrome virus, human coronavirus OC43, chicken infectious bronchitis virus, porcine infectious gastroenteritis virus, porcine epidemic diarrhea virus, and murine hepatitis virus, can cause severe diseases in humans and livestock. The severe acute respiratory syndrome coronavirus 2 is infecting millions of human beings with high morbidity and mortality worldwide, and the multiplicity of swine epidemic diarrhea coronavirus in swine suggests that coronaviruses seriously jeopardize the safety of public health and that therapeutic intervention is urgently needed. Currently, the most effective methods of prevention and control for coronaviruses are vaccine immunization and pharmacotherapy. However, the emergence of mutated viruses reduces the effectiveness of vaccines. In addition, vaccine developments often lag behind, making it difficult to put them into use early in the outbreak. Therefore, it is meaningful to screen safe, cheap, and broad-spectrum antiviral agents for coronaviruses. This review systematically summarizes the mechanisms and state of anti-human and porcine coronavirus drugs, in order to provide theoretical support for the development of anti-coronavirus drugs and other antivirals.

Search for zoonotic camel infections posing a potential human health threat in Kazakhstan

Worldwide studies have shown the importance of controlling the spread of zoonotic infections. In recent years, new pandemic strains of coronaviruses in camels have been identified, which necessitates regular monitoring of the state of viral populations of this animal. The research scope is to identify the spectrum of viral and bacterial populations circulating in camels in Kazakhstan posing threat to human and animal health, their molecular genetic studies. Virological and molecular-genetic methods were used: taking biological samples from camels, extracting nucleic acids from them, obtaining libraries for massive parallel sequencing, bioinformatic analysis of the data obtained and serological tests. Massive parallel sequencing revealed the viral contigs classified into 3 large genera: Pestivirus, Circovirus, and Hepevirus. Of particular interest is the discovery of short sequences similar to those of the hepatitis E virus, which requires further deeper studies in this direction. Serological studies of camels from the Mangystau region did not reveal antibodies to the Middle East respiratory syndrome virus (MERS-CoV), which shows their absence in active circulation or much time has been passed since their possible presence in camels. The study of viral metagenomes of camels in the region close to the Middle East is an important task of scientific research. A metagenomic study will allow to detect not only coronaviruses, but also to analyze other and unknown viral infections that are important both for agriculture and for the health of the human population.

Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is spreading worldwide with different clinical manifestations. Age and comorbidities may explain severity in critical cases and people living with human immunodeficiency virus (HIV) might be at particularly high risk for severe progression. Nonetheless, current data, although sometimes contradictory, do not confirm higher morbidity, risk of more severe COVID-19 or higher mortality in HIV-infected people with complete access to antiretroviral therapy (ART). A possible protective role of ART has been hypothesized to explain these observations. Anti-viral drugs used to treat HIV infection have been repurposed for COVID-19 treatment; this is also based on previous studies on severe acute respiratory syndrome virus (SARS-CoV) and Middle East respiratory syndrome virus (MERS-CoV). Among them, lopinavir/ritonavir, an inhibitor of viral protease, was extensively used early in the pandemic but it was soon abandoned due to lack of effectiveness in clinical trials. However, remdesivir, a nucleotide analog that acts as reverse-transcriptase inhibitor, which was tested early during the pandemic because of its wide range of antiviral activity against several RNA viruses and its safety profile, is currently the only antiviral medication approved for COVID-19. Tenofovir, another nucleotide analog used extensively for HIV treatment and pre-exposure prophylaxis (PrEP), has also been hypothesized as effective in COVID-19. No data on tenofovir’s efficacy in coronavirus infections other than COVID-19 are currently available, although information relating to SARS-CoV-2 infection is starting to come out. Here, we review the currently available evidence on tenofovir’s efficacy against SARS-CoV-2.

COVID-19 transmission, vulnerability, persistence and nanotherapy: a review

End 2019, the zoonotic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), named COVID-19 for coronavirus disease 2019, is the third adaptation of a contagious virus following the severe acute respiratory syndrome coronavirus in 2002, SARS-CoV, and the Middle East respiratory syndrome virus in 2012, MERS-CoV. COVID-19 is highly infectious and virulent compared to previous outbreaks. We review sources, contagious routes, preventive measures, pandemic, outbreak, epidemiology of SARS-CoV, MERS-CoV and SARS-CoV-2 from 2002 to 2020 using a Medline search. We discuss the chronology of the three coronaviruses, the vulnerability of healthcare workers, coronaviruses on surface and in wastewater, diagnostics and cures, and measures to prevent spreading.

The SARS-CoV-2 receptor and other key components of the Renin-Angiotensin-Aldosterone System related to COVID-19 are expressed in enterocytes in larval zebrafish.

ABSTRACTPeople with underlying conditions, including hypertension, obesity, and diabetes, are especially susceptible to negative outcomes after infection with coronavirus SARS-CoV-2, which causes COVID-19. Hypertension and respiratory inflammation are exacerbated by the Renin-Angiotensin-Aldosterone System (RAAS), which normally protects from rapidly dropping blood pressure via Angiotensin II (Ang II) produced by the enzyme Ace. The Ace paralog Ace2 degrades Ang II, counteracting its chronic effects, and serves as the SARS-CoV-2 receptor. Ace, the coronavirus, and COVID-19 comorbidities all regulate Ace2, but we do not yet understand how. To exploit zebrafish (Danio rerio) to help understand the relationship of the RAAS to COVID-19, we must identify zebrafish orthologs and co-orthologs of human RAAS genes and understand their expression patterns. To achieve these goals, we conducted genomic and phylogenetic analyses and investigated single cell transcriptomes. Results showed that most human RAAS genes have one or more zebrafish orthologs or co-orthologs. Results identified a specific type of enterocyte as the specific site of expression of zebrafish orthologs of key RAAS components, including Ace, Ace2, Slc6a19 (SARS-CoV-2 co-receptor), and the Angiotensin-related peptide cleaving enzymes Anpep (receptor for the common cold coronavirus HCoV-229E), and Dpp4 (receptor for the Middle East Respiratory Syndrome virus, MERS-CoV). Results identified specific vascular cell subtypes expressing Ang II receptors, apelin, and apelin receptor genes. These results identify genes and cell types to exploit zebrafish as a disease model for understanding mechanisms of COVID-19.

Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen.

Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro and have identified 62 additional compounds with IC50 values below 1 μM and profiled their selectivity toward chymotrypsin and 3CL-Pro from the Middle East respiratory syndrome virus. A subset of eight inhibitors showed anticytopathic effect in a Vero-E6 cell line, and the compounds thioguanosine and MG-132 were analyzed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Å, showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.

Carbon-based nanomaterials for viral infection management.

Carbon-based nanomaterials such as graphene and nanodiamonds have demonstrated impressive physical and chemical properties, such as remarkable strength, corrosion resistance, and excellent electrical and thermal conductivity, and stability. Because of these unique characteristics, carbon nanomaterials are explored in a wide range of fields, including the diagnosis and treatment of viruses. As there are emerging concerns about the control of virus including Middle East respiratory syndrome virus (MERS), severe acute respiratory syndrome coronavirus (SARS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), this review highlights the recent development of carbon based-nanomaterials for the management of viral infections.

Comparison of Clinical, Haematological, Biochemical Findings and Significance of Co-morbidities amongst COVID-19 Positive Survivors and Nonsurvivors

Introduction: Corona virus 2019 was first isolated in 1960. Middle East Respiratory Syndrome virus (MERS) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) also belongs to Corona viridae family. Human Coronavirus causes fever, cough, fatigue, respiratory infection and abdominal symptoms. This virus has a strong affinity to human respiratory receptors and transmits rapidly. Since the virus has spread around the world and has acquired features of emergency, WHO declared it as a pandemic in March 2020. Aim: To study the clinical, haematological, biochemical findings and significance of co-morbidities amongst COVID-19 positive survivors and nonsurvivors. Materials and Methods: A retrospective cohort study was done at Chattrapati Shivaji Subharti Hospital (CSSH), Meerut, Uttar Pradesh, a level 3 COVID-19 Hospital from mid-June to end of August 2020 including 140 COVID-19 positive patients selected randomly. Patients were categorised into asymptomatic and symptomatic. Symptomatic were further divided into survivors and nonsurvivors. Haematological and biochemical parameters were analysed amongst survivors and nonsurvivors, with calculation of significant p-value. Results: Out of total 140 patients, 37/140 patients (26%) were asymptomatic and 103/140 (74%) symptomatic. Amongst symptomatic, survivors were 78/140 (56%) and nonsurvivors were 25/140 (18%) of total positive patients. Out of 37/140 (26%) asymptomatic patients, majority were in the age group 21-30 years 14/140 (10%) with female preponderance 10/140 (7.1%). Out of 78/140 (56%) survivors, majority were in 51 to 60 years age group, with male predominance17/140 (18.6%). Amongst 25/140 (18%) nonsurvivors most common affected age group was 51 to 60 years 10/140 (7.1%). Most common symptoms in survivors was cough (51/78 patients; 65%) and fever (35/78 patients; 45%). In Nonsurvivors, pneumonia was seen in 100% (25/25) patients. Out of 23/25 (92%) patients presented with fever, 19/25 (76%) had breathlessness, 16/25 (64%) had myalgia, 9/25 (36%) had cough, 5/25 (20%) presented with vomiting or pain in abdomen. Amongst nonsurvivors, Total Leucocyte Count (TLC), Absolute Neutrophil Count (ANC), Neutrophil Lymphocyte Ratio (NLR), urea, serum creatinine, serum bilirubin, Aspartate Amino Transferase (AST) and Alanine Amino Transferase (ALT) were significantly raised as compared to survivors (p<0.01); meanwhile platelet count and Platelet Lymphocyte Ratio (PLR) in nonsurvivors was significantly lower than survivors (p<0.01). Most common comorbidity was diabetes in 12/25 (48%) and hypertension in 6/25 (24%) among nonsurvivors. Conclusion: COVID-19 infection more likely affects older men with co-morbidities like diabetes mellitus and hypertension and can rapidly progress to pneumonia, Acute Respiratory Distress Syndrome (ARDS) and septic shock. Certain haematological and biological parameters have been found to be in concordance with increased mortality which can be reduced by early identification of these parameters.

Caring for Cancer Patients during Corona Pandemic-(COVID-19)-A Narrative Review.

Background Coronavirus disease 2019, the third pandemic of 21st century which has brought the whole world under panic, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a zoonotic beta coronavirus sharing phylogenetic, genomic similarities with SARS virus and Middle East Respiratory Syndrome virus. Specific Concerns Cancer patients are at double the risk than normal patients since these patients are at immunocompromised state. WHO guidelines advice the patients to plan only emergency hospital visits only till the pandemic persists. Should meet patient/visitors in a well-ventilated room or outdoors and maintain at least 2 m distance between the visitor/patients. It also encourages the patient to refill the prescribed medications in well advance and to stay physically active, if possible. Discussion The World Health Organizations’ isolate, trace, test, treat policy needs to be followed to protect these high-risk patients from this global pandemic.]

Geometric architecture of viruses.

In the current SARS-CoV-2 disease (COVID-19) pandemic, the structural understanding of new emerging viruses in relation to developing effective treatment and interventions are very necessary. Viruses present remarkable differences in geometric shapes, sizes, molecular compositions and organizations. A detailed structural knowledge of a virion is essential for understanding the mechanisms of capsid assembly/disassembly, antigenicity, cell-receptor interaction, and designing therapeutic strategies. X-ray crystallography, cryo-electron microscopy and molecular simulations have elucidated atomic-level structure of several viruses. In view of this, a recently determined crystal structure of SARS-CoV-2 nucleocapsid has revealed its architecture and self-assembly very similar to that of the SARS-CoV-1 and the Middle-East respiratory syndrome virus (MERS-CoV). In structure determination, capsid symmetry is an important factor greatly contributing to its stability and balance between the packaged genome and envelope. Since the capsid protein subunits are asymmetrical, the maximum number of inter-subunit interactions can be established only when they are arranged symmetrically. Therefore, a stable capsid must be in a perfect symmetry and lowest possible free-energy. Isometric virions are spherical but geometrically icosahedrons as compared to complex virions that are both isometric and helical. Enveloped icosahedral or helical viruses are very common in animals but rare in plants and bacteria. Icosahedral capsids are defined by triangulation number (T = 1, 3, 4, 13, etc.), i.e., the identical equilateral-triangles formed of subunits. Biologically significant defective capsids with or without nucleic acids are common in enveloped alpha-, flavi- and hepadnaviruses. The self-assembling, stable and non-infectious virus-like particles have been widely exploited as vaccine candidates and therapeutic molecules delivery vehicles.

Computational Studies of SARS-CoV-2 3CLpro: Insights from MD Simulations.

Given the enormous social and health impact of the pandemic triggered by severe acute respiratory syndrome 2 (SARS-CoV-2), the scientific community made a huge effort to provide an immediate response to the challenges posed by Coronavirus disease 2019 (COVID-19). One of the most important proteins of the virus is an enzyme, called 3CLpro or main protease, already identified as an important pharmacological target also in SARS and Middle East respiratory syndrome virus (MERS) viruses. This protein triggers the production of a whole series of enzymes necessary for the virus to carry out its replicating and infectious activities. Therefore, it is crucial to gain a deeper understanding of 3CLpro structure and function in order to effectively target this enzyme. All-atoms molecular dynamics (MD) simulations were performed to examine the different conformational behaviors of the monomeric and dimeric form of SARS-CoV-2 3CLpro apo structure, as revealed by microsecond time scale MD simulations. Our results also shed light on the conformational dynamics of the loop regions at the entry of the catalytic site. Studying, at atomic level, the characteristics of the active site and obtaining information on how the protein can interact with its substrates will allow the design of molecules able to block the enzymatic function crucial for the virus.

Epidemiology, Treatment and Microbiological Surveillance of SARS-CoV-2

Coronaviruses (CoV) belong to Coronaviridiae family that cause deadly diseases in humans or animals. These viruses are enveloped and have single stranded positive-sense large RNA genome. Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) causes deadly pandemic coronavirus disease-2019 (COVID-19) in humans. It is affecting every aspect of humans’ daily life. The symptoms of COVID-19 include fever, loss of smell, shortness of breath, cough, muscles pain, chest pain, and kidney failure that occurs in severe conditions. The virus has spread throughout the world. In India, the estimated number of infected people is more than 1.5 lakh with less fatality rate 2.87% on May 27, 2020 as per the Ministry of Health and Family Welfare data. The studies suggest that virus has been considered descended from the previous viruses as severe acute respiratory syndrome corona virus (SARS-CoV), Middle East respiratory syndrome virus (MERS) human and bat corona viruses. Currently, vaccine developments are under clinical trials. The management of emerging infectious diseases is a challenging task. It requires much improved microbiological surveillance system to track and predict the virus infections. The proper study and predictions based on screening of various sources of infection may help us to manage the challenging infections in future. The present review summarizes the characteristics of virus, disease symptoms, epidemiology, transmission, treatment and microbiological surveillance of pandemic COVID-19.

Fetomaternal Outcome in Women with COVID-19 in a COVID Designated Hospital in Lahore, Pakistan

<p><strong>Background and Objective:</strong> The pandemic caused by Coronavirus disease-2019 (COVID-19) is notably becoming similar to severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome viruses (MERS) for causing poor feto-maternal outcome. There is not much data available about COVID-19 during pregnancy in Pakistan therefore the objective of this study is to determine maternal and fetal outcome in pregnant women affected with COVID-19 and to find out frequency of vertical transmission. <strong>Methods: </strong>This descriptive case series was conducted from 1st April 2020 to 10th May 2020 at Department of Obstetrics and Gynecology, COVID ward, Sir Ganga Ram Hospital, Lahore. A total of 20 women were included in the study that were found positive for viral RNA by Real-Time Reverse TranscriptionPolymerase Chain Reaction (rRT-PCR) of nasopharyngeal specimens. Demographics, duration of gestation, fetomaternal outcome and vertical transmission were noted in the respected proformas. The data was analyzed using Statistical Package for Social Sciences version 20. <strong>Results:</strong> The mean age of these gravid females was 29.3 ± 4.17 years. The mean gravidity was 2.60 ± 1.14 and mean gestational age was 29 ± 9.53 weeks. Among 20 patients, 4(20%) were primigravida, 5(25%) females were gravida 2 and remaining 11(55%) cases were gravida 3 and 4. The most common presenting complaints were fever followed by dry cough, myalgia and shortness of breath. Nine patients were delivered by lower segment cesarean section in which fetal distress was observed in 5(55.6%) newborns and 1(10%) newborn was preterm. Among all newborns, 02 developed respiratory distress syndrome and were admitted in pediatric intensive care unit. All pharyngeal swabs of newborns were negative at 12 and 24 hours of life. <strong>Conclusion:</strong> COVID-19 in pregnant females is not different than in general population. The fetomaternal outcome is usually good and there is no evidence of vertical transmission in any newborn.</p>

MERS-CoV Spike Protein Vaccine and Inactivated Influenza Vaccine Formulated with Single Strand RNA Adjuvant Induce T-Cell Activation through Intranasal Immunization in Mice.

The effectiveness of vaccines is enhanced by adding adjuvants. Furthermore, the selection of an inoculation route depends on the type of adjuvant used and is important for achieving optimum vaccine efficacy. We investigated the immunological differences between two types of vaccines—spike protein from the Middle East respiratory syndrome virus and inactivated influenza virus vaccine, in combination with a single-stranded RNA adjuvant—administered through various routes (intramuscular, intradermal, and intranasal) to BALB/c mice. Intramuscular immunization with the RNA adjuvant-formulated spike protein elicited the highest humoral immune response, characterized by IgG1 and neutralizing antibody production. Although intranasal immunization did not elicit a humoral response, it showed extensive T-cell activation through large-scale induction of interferon-γ- and interleukin-2-secreting cells, as well as CD4+ T-cell activation in mouse splenocytes. Moreover, only intranasal immunization induced IgA production. When immunized with the inactivated influenza vaccine, administration of the RNA adjuvant via all routes led to protection after viral challenge, regardless of the presence of a vaccine-specific antibody. Therefore, the inoculation route should depend on the type of immune response needed; i.e., the intramuscular route is suitable for eliciting a humoral immune response, whereas the intranasal route is useful for T-cell activation and IgA induction.

Decontaminating the Nose, Mouth and Throat of SARS-CoV-2 with Povidone-Iodine – Aren’t We Missing Out on Very Effective Prevention and Prophylactic Tools in the War Against the COVID-19 Pandemic?

Background: An outbreak of a new coronavirus, the SARS-CoV-2 (or COVID-19) has resulted in more than two million infected people and tens of thousands of deaths (the situation quickly evolves on daily basis). Fortunately, majority of patients experience only mild upper respiratory tract symptoms, or no symptoms at all, loss of smell and taste being the predominant complaint.But, unfortunately, even asymptomatic individuals can unknowingly spread the infection, which makes the pandemic very difficult to get under control. While lockdowns for entire country populations have shut down economies and international trade, the WHO has warned they may not be enough despite their high long-term economic and social costs.However, little or no scientific information has circulated reviewing already existing effective science- and evidence-based preventive/prophylactic measures that "kill" SARS-CoV-1 and are likely also to inactivate the current SARS- CoV-2.Our personal communication aims to fill this void.Method: First, we review the scientific literature and the evidence on preventive/prophylactic measures that neutralize SARS-CoV-1 virus. Second, our analysis looks into the scientific evidence on the use of povidone-iodine (PVP-I) in mouthwash/gargling/spray forms, as these represent the only innovatively developed, tested and available practical solution to inactivate SARS-CoV viruses (e.g. SARS-CoV-1, Middle-East Respiratory Syndrome virus or MERS, and SARS-CoV-2).Findings: Multiple evidence (mainly in vitro/cell cultures) demonstrate that the use of povidone-iodine (PVP-I) inactivates SARS-CoV-1 in matter of seconds. Preliminary test results suggest it may also similarly “kill” the current new SARS-CoV-2.Update [1 January 2021]: new evidence confirms that PVP-I inactivates SARS-CoV-2.Discussion: The use of PVP-I for decontamination of the nose/mouth/throat has a well-established tolerability profile, is low-cost and has limited downside risks. It is an evidence-based and highly cost-effective health intervention. Our analysis suggests that PVP-I utilization merits being considered as an additional preventive measure (in clinical and in population settings) against getting infected by, and infecting others with, the current SARS-CoV-2 virus. However, the real-world evidence (in vivo) of their effectiveness in the form of mouthwashes/gargles/sprays for the decontamination of the nose, mouth and throat, is rather scarce. FOR UP-TO-DATE VERSION, DO NOT CIRCULATE/RE-PUBLISH THE PDF FILE BUT SHARE THIS LINK: https://ssrn.com/abstract=3579425

Hematologic Values of Jamaican Fruit Bats (Artibeus jamaicensis) and the Effects of Isoflurane Anesthesia.

Jamaican fruit bats (Artibeus jamaicensis) are used as an animal model for several viruses, including Middle East respiratory syndrome virus, dengue virus, Zika virus, and Tacaribe virus. However, despite ongoing studies regarding these pathogens, little is known regarding the bats' normal physiology. In this study, phlebotomy of the propetagial (cephalic) vein was performed to establish baseline hematologic parameters in an apparently healthy, captive population of Jamaican fruit bats. Furthermore, we compared results from physically restrained and isoflurane-anesthetized bats. Our findings indicate significant increases in WBC count, lymphocytes, and monocytes in the anesthetized bats. However, RBC and platelet parameters were not different between the 2 groups. This information on the normal hematologic parameters of Jamaican fruit bats, adds to our overall understanding of the normal physiology of this species, and expands our knowledge on bat species in general.

Data sharing and outbreaks: best practice exemplified

Data sharing and outbreaks: best practice exemplified

The US Military Commitment to Vaccine Development: A Century of Successes and Challenges.

The US military has been a leading proponent of vaccine development since its founding. General George Washington ordered the entire American army to be variolated against smallpox after recognizing the serious threat that it posed to military operations. He did this on the recommendation from Dr. John Morgan, the physician-in-chief of the American army, who wrote a treatise on variolation in 1776. Although cases of smallpox still occurred, they were far fewer than expected, and it is believed that the vaccination program contributed to victory in the War of Independence. Effective military force requires personnel who are healthy and combat ready for worldwide deployment. Given the geography of US military operations, military personnel should also be protected against diseases that are endemic in potential areas of conflict. For this reason, and unknown to many, the US military has strongly supported vaccine research and development. Four categories of communicable infectious diseases threaten military personnel: (1) diseases that spread easily in densely populated areas (respiratory and dysenteric diseases); (2) vector-borne diseases (disease carried by mosquitoes and other insects); (3) sexually transmitted diseases (hepatitis, HIV, and gonorrhea); and (4) diseases associated with biological warfare. For each category, the US military has supported research that has provided the basis for many of the vaccines available today. Although preventive measures and the development of drugs have provided some relief from the burden of malaria, dengue, and HIV, the US military continues to fund research and development of prophylactic vaccines that will contribute to force health protection and global health. In the past few years, newly recognized infections with Zika, severe acute respiratory syndrome, Middle East respiratory syndrome viruses have pushed the US military to fund research and fast track clinical trials to quickly and effectively develop vaccines for emerging diseases. With US military personnel present in every region of the globe, one of the most cost-effective ways to maintain military effectiveness is to develop vaccines against prioritized threats to military members’ health.

Herd immunity: hyperimmune globulins for the 21st century

Recent headlines, including outbreaks of Ebola virus disease in urban west Africa, the intercontinental transmission of Middle East respiratory syndrome virus (MERS) from the Arabian Peninsula to South Korea, and the emergence of Zika virus as a fetal neurotoxic agent, highlight the global threat posed by emerging infectious diseases in an increasingly connected world.