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Penicillin was discovered by Alexander Fleming in 1928. However, the purification and production process was not dependable until the early 1940s when scientists Howard Florey and Ernst Chain built on Fleming’s original findings. In 1942, the first American patient was treated with the antimicrobial drug. Penicillin inhibits cell wall synthesis in certain bacterial species, resulting in cell death. Since then, multiple targets for antimicrobial action have been identified including inhibition of protein synthesis, nucleic acid synthesis, and metabolic pathways. Researchers then and now have sought to synthesize new chemical structures to treat bacterial infections via the aforementioned targets. It is almost incomprehensible that less than 80 years ago, antibiotics were unknown in everyday healthcare. Even more notable, is rate at which antibiotics are becoming insufficient in treating common bacterial infections. In addition to random mutation, several mechanisms developed to transfer novel genetic info to bacteria within and between species. Because bacteria multiply exponentially with quick turnover, genetic acquisitions that confer resistance can build rapidly in a population.

A case study following the development of antibiotic resistance in strains of Staphylococcus aureus reveals the fight of bacteria against our “miracle drugs.” S. aureus is a gram positive coccus, appearing in grape like clusters under a microscope. Although many people are normal carriers of this bacteria, it poses a serious threat to immunocompromised patients and is the leading cause of healthcare-acquired infections. This study outlines the frequently changing antibiotic resistance profile of S. aureus and some surveillance methods in place. The very first test of penicillin was given to a 43-year-old English policeman with a life-threatening S. aureus infection from rose thorn scratch near his mouth. After the injection, he made a remarkable recovery over a few days. When the small supply ran dry, his infection unfortunately returned in full form. However, 95.2% of the S. aureus recovered from HIV patients in the linked study was highly penicillin resistant, 84.6% were cephalexin resistant, and in the year 2017, 86% were methicillin resistant (compared to 51.8% in 2012). In today’s times, the policeman would not exhibit any recovery after an injection of penicillin. From year 0 to year 78, the bacteria have acquired an unimaginable number of genetic changes conferring protection, and serving as an amazing example of evolution in action. Methicillin resistant S. aureus (MRSA) currently is most threatening in healthcare settings.

The misuse of antibiotics, in humans and animals, dramatically increases the rate at which bacterial populations demonstrate new forms of resistance. When a group of bacteria is exposed to an inhibiting or bactericidal substance, selective pressure is exerted against susceptible strains. The few resistant individuals will then clonally expand, rendering a subsequent round of the antibiotic useless. On a large scale, when antibiotics are used unnecessarily, this selective pressure persists, constantly singly out the most fit bacteria to drive future populations. The WHO expresses the urgency with which antimicrobial needs to be addressed. The CDC also outlines actions that people can take in their everyday lives to reduce the speed at which antimicrobial resistance is developing. Antibiotics are crucial to continuing current health standards and protect a huge community of susceptible individuals from life-threatening infections. 78 years of antibiotics is not a lot. Global action is necessary to ensure the continued effectiveness of the world’s miracle drugs.

Bordetella pertussis (pictured below) is a gram negative, rod-shaped, obligate aerobe bacterium that causes pertussis, better known as whooping cough. Protection against this disease, which presents in three stages and is characterized by a “whooping” cough that persists for 4-8 weeks, is included in the DTaP vaccine for young children (0-6 years) and the TDaP vaccine for teens and adults. Four rounds of vaccination are administered prior to 18 months, once between the ages of 4-6, once between ages 11-12, and once during pregnancy (weeks 27-36). This sequence of vaccinations indicates a low strength immune response per injection. In 1997 the vaccine was altered from a form containing whole inactivated bacterial cells to DTaP which instead contains subunits (acelluar, aP vaccine) and is given in combination with tetanus and diphtheria boosters. The cellular vaccination produced an effective immune response, dramatically decreasing the incidence of pertussis, but had severe side effects. DTaP has no notable side effects but elicits a weaker immune response.

In recent years, the extent of waning immunity has been uncovered as outbreaks in fully vaccinated individuals continue to occur, in increasing amounts since the aP vaccine’s introduction (view trends). My younger sister, fully vaccinated, contracted the disease in 2015 during middle school. It was transmitted via respiratory droplets, with less severe presentation, to our cousin of the same age. My sisters progression aligned precisely with the 3 characteristic stages: catarrhal stage (1-2 weeks of typical upper respiratory symptoms, with low fever), paroxysmal stage (2-4 weeks of a violent whooping cough inducing vomiting and difficulty breathing), and convalescent stage (recovery with coughing attacks gradually decreasing). It seemed impossible, that after 6 vaccinations, the disease could present so severely in a young healthy individual. The danger for newborns and immunocompromised individuals can be thus inferred. Additionally, it was interesting that the bacterium was only transmitted to one other family member who was on the exact same vaccination timeline. My grandfather (a pediatrician), and my father (an internal medicine doctor), suspected that the pre-teen booster they both received conferred lower immunity in comparison to boosters of other years. These instances observed in my family correlate with the spike (above graph) between 2010 and 2018.

Besides the inherent weakness in the vaccine containing antigen rather than whole cells, there is also some evidence that B. pertussis has undergone vaccine induced selection. Researchers are searching for alternative forms to the aP, that might prevent waning immunity and outbreaks. The live attenuated BPZE1 intranasal vaccine is currently undergoing trials. This form is noted to prevent nasal colonization of B. pertussis, reducing transmission and potentially disease incidence. Limited side effects were noted in the preliminary human experiments (results posted January 2, 2020). The DTaP and TDaP vaccines still significantly reduce disease risk for pertussis when unvaccinated, partially vaccinated, and fully vaccinated individuals are compared. However, there is always room for improvement. Reducing the ability of transmission via the nasal route would positively inhibit the disease threats to infants <1, to whom the disease is most fatal.

Poliomyelitis and polioencephalitis are infections caused by an enterovirus of the Picornaviridiae family presenting as a non-enveloped, icosahedral, single stranded, positive sense RNA virus. This detergent-resistant particle enters through the mouth via fecal-oral transmission (most-common) and inhalation of respiratory droplets (less-common). Once bound to the CD155 human cell receptor, the virus lives in the throat and intestines of infected individuals. Upon replication and viremia, the virus is able to target the nervous system and the anterior horns of spinal or brain stem grey matter causing paralysis or brain inflammation in many cases. Usual symptoms present in a 2-5 day period, but the virus sheds for up to two weeks in both the incubation and convalescent periods, adding to the virulence and historical rapid spread of this microbe in unsanitary and overcrowded areas. Between the late 1940s and early 1950s, polio crippled around 35,000 people in the U.S. alone, making it one of the most feared diseases of the 20th century. Because this virus only has a human reservoir, a vaccine was introduce in 1955, and only three wild serotypes are observed, it is the perfect candidate for vaccine induced eradication.

On Saturday, October 24th 2019, officials announced the worldwide eradication of wild poliovirus type 3 (WPV3), adding to the previous triumph of eliminating WPV2. The final step is to end the circulation WPV1 in Afghanistan and Pakistan and the resistant vaccine-derived polioviruses which have mutated beyond the constraints of the vaccine. Only when this mutant form circulates in an underimmunized population for 12-18 months is it occasionally able to reacquire neurovirulence from its original live attenuated form. This feat will require the intense commitment of these countries and their partners. Here, the progress towards polio eradication is vehemently tracked, including a summary of new viruses this week. To date in 2020, there have been 12 documented WPV1 cases all occurring in Pakistan.

There are two forms of the poliovirus vaccine: inactivated polio vaccine (IPV) and oral polio vaccine (OPV). IPV is the only vaccine given in the US since 2000, and the shot is recommended by the CDC in four doses throughout a child’s first 18 months. OPV is no longer licensed or available in the U.S. because of the risk associated in creating vaccine-derived polioviruses, but is frequently used in other countries because it can be easily given by volunteers. Because IPV is not a “live” vaccine, the contents do not replicate in the body and therefore are not able to spread and mutate. Additionally, it poses no threat to immunocompromised individuals. However, the vaccine confers low immunity in the intestines and asymptomatic infected people can spread wild-type virus. For this reason, IPV cannot be used in areas where outbreak control is urgent or immunity and sanitation are low. OPV contains attenuated polioviruses that actively replicate in the intestines, allowing a large protective immune response to surmount and interrupt person to person transmission. Additionally, the shedding of this attenuated form can passively spread immunity in a community where fecal-oral transmission frequently occurs due to poor hygiene and sanitation. The public reaction to polio today proves the immense success of these vaccines. Fear is not rampant and suffering significantly reduced. The demise of the last poliovirus is in sight.

Who thinks vaccines are amazing!? (Me.) Who loves to have needles inserted in them!? (NOT me.) In a previous post the advent of the anti-vaxxer mobilization was explored in the context of Andrew Wakefield’s “scientific” study. Despite his observations being dis-proven multiple times, the anti-vaxxer movement lives on. Selective hearing is in human nature. For anyone that despises the needles, doctors offices, and the screaming children associated with vaccines, it would be easiest to adopt the stance that prevents your interaction with them. But where is vaccine misinformation being funneled from? Experts have identified social media.

In the peak of Andrew Wakefield’s sentiments, social media did not play as large a role in public life. Most young people, including young parents, are never without easy access to Facebook, Twitter, and Instagram, where unqualified users amplify their opinions on vaccines. The term “vaccine hesitancy,” defined by WHO as a “delay in acceptance or refusal of vaccines despite availability of vaccination services,” perhaps better represents the situation occurring in developed nations such as the U.S. Parents who read a disturbing message about vaccines on Facebook may subconsciously (or consciously) delay vaccinating their children. The problem with this lies in herd immunity. Failing to reach immunization thresholds by just a few percentage points can cause massive outbreaks of dangerous preventable diseases such as chickenpox, measles, mumps and rubella (MMRV vaccine). Survey data shows a steady decline in the perceived importance of vaccines since 2001. A correlation exists between those most likely to be on social media and those populations with the lowest % declaring the importance of vaccines. Overall, 79% of people are saying they have heard “a great deal” or “fair amount” about the disadvantages of vaccines (as compared with 39% in 2001).

One interesting note from the linked survey (above), is the movement of Americans away from the idea that vaccines induce autism (10%). Other vague and unidentified reasons are now plaguing public attitudes towards vaccines. That middle of the road group (neither die-hard anti-vaxxer or die-hard vaccinator) is where social media exerts the greatest influence. With only 12% of American’s having proficient health literacy, the majority of people are prone to gaining vaccine information from internet sources. In addition to the dialogue based approach, national committees should be taking advantage of social media outlets. The facts need to be published in a way that is understandable and believable to the general public. Here you can read Taylor Sharp’s vaccine thread, that provides a great example of how to target an audience in need of vaccine education. Historical and health awareness alike is necessary to combat the recent climb in vaccine hesitancy. Reverse the trends of social media, and make the internet a positive outlet!

The genes and environment of every person has created a unique ecosystem in which bacteria dwell and thrive. The microbiome, or the colonized microorganisms within and on the human body, has influenced every aspect of medical research in recent years as scientists are realizing the expansive roles bacteria play in metabolism and overall health. However, the differences in host microbial conditions are making it difficult to identify what a “healthy” microbiome consists of. One important aspect of the mutualistic relationships between humans and their microbiomes presents in the intestinal tract. Because so much research is conducted in the Western and developed worlds, there is a significant bias towards the health standards of particular nations. The conclusion being, a healthy microbiome in one context, could be completely useless in another.

The figure above demonstrates the differences in diets across multiple nations. What a person eats affects what nutrients are being funneled to resident intestinal bacteria and therefore dictates which species thrive. Additionally, because the microbiome is passed in part via vertical transmission during birth, the lineages of bacterial colonization are somewhat consistent within families and general environmental conditions. With these observations, it can be concluded that healthy bacterial profiles will differ greatly between individuals. Because this variability has been passively identified, it begs the question: should people be taking action to actively manipulate their microbiome to better their health? To answer this question, however, researchers must determine the pro and con actions of typical resident microbiota.

Antibiotic overuse demonstrates a situation in which resident microbiota are actively altered, but with negative effects. Infection with antibiotic-resistant bacteria results in almost 50,000 deaths a year in the U.S. alone. These drugs exert selective pressure for pathogens that are able to resist the antibiotic arsenal. Because antibiotics will inherently wipe out many bacteria in the body unintentionally, it also decreases the competition for colonization faced by pathogens. Normal flora can affect protect the body passively by way of increasing competition for resources, but also some species have a direct inhibitory effect via secretions. For example, Bacteriodes species can produce peptides inhibiting C. diff growth and colonization. Further exploration is necessary to determine the health benefits of normal flora, across different environments and cultures, in terms of normal metabolism and protective action. Advances in determining how to best nourish a healthy microbiome, tailored to individuals, could signify great progress in medical practice.

Since the previous post concerning the circulating 2019-nCoV, researchers have been busy trying to answer some of the many unknowns about this novel virus. As of January 31st, 2020 the US declared a public health emergency, with a total of 12 confirmed cases. However, the fear lies in the human-to-human transmission that is suspected to occur through respiratory droplets. This form of transmission means that a healthy person must somehow transfer a droplet containing virions from an infected person to the appropriate portal of entry, through the respiratory tract, either by inhaling the droplets from a nearby contagious person (1-5 ft range in the diagram above) or moving them with the hands. The estimated R-naught value for 2019-nCoV is 2.2, indicating the average number of people that will contract the disease from one contagious person. This number indicates that close contact is necessary, and that prevention is possible with better hand-washing and mouth covering technique.

From this report, it appears that the virus can be spread during its incubation period as several German workers were passed the disease by an asymptomatic Chinese business contact. This type of evidence is what pushes the US to take great precaution, and continue the declaration of a public health emergency even with a low number of confirmed cases. Because the incubation period is still unknown, with an estimated range of 2-14 days, it will be difficult to identify those infected and potentially spreading the disease to their contacts. That same report from Germany also found a high viral content in the sputum of one patient during the convalescent period. Therefore, even when an infected person is in the recovery phase, transmission is still possible.

With the death toll climbing in China, now at 636, the investigation into antiviral drugs is heightening. This article displays the effectiveness, in vitro, of Remdesivir and Chloroquine. Remdesivir has shown promise against an array of RNA viruses, by incorporating into nascent viral RNA chains and causing early termination. Chloroquine, used commonly as an anti-malarial and autoimmune disease drug, and works by increasing the endosomal pH required for cell-virus fusion, and interfering with glycosylation of host cellular receptors for the virus. Since both of these have already gone through appropriate safety testing, they would be easy options for testing against the 2019-nCoV. Some HIV protease inhibitors are also being considered, since the 2019-nCoV’s viral protease is noted to be essential for its replication. This kind of research is crucial in halting the death toll, whether the rate of transmission subsides or not.

The question of the passage of transmission, mentioned in the previous post, of this originally zoonotic disease in the Wuhan market has also been further investigated. Although the work is not published, researchers have recovered coronaviruses with 99% genetic similarity to the circulating 2019-nCoV from the pangolin (pictured above). The illegal trading of this animal is widespread. Therefore, even though it is not listed as a product at the Wuhan market, its presence there is possible. Further investigation is needed to confirm this observation. If identification is confirmed, at least one end of the transmission loop can be closed.

Every year, the U.S. engages in a battle. The enemy trickles in when the leaves start to change, and doesn’t make the extent of its presence known until late winter. The soldiers never quite look the same, with modified weapons and a myriad of disguises. All summer, the good guys guess how to best defend their country. But, the same conditions of attack surface in the population year after year: the fever, sore throat, cough, muscle aches, and fatigue of the Influenza Virus. The guessing game, in terms of vaccine production, that scientists play impacts the severity of flu burden on the U.S. population. Comparing the 2017-2018 season (61,000 influenza-related deaths) with the 2018-2019 (34,200 influenza-related deaths) season displays the massive variability in disease incidence and mortality. The CDC has estimated 12,00 influenza-related deaths so far this season (2019-2020). Other contributing factors are overall national attitudes towards vaccines and knowledge of the threat of influenza.

Depicted above is a generic flu virus, showing its enveloped structure and negative-sense, single-stranded RNA genome, segmented into either 7 (type C) or 8 (type A and B) pieces. Embedded in the envelope of type A and B are two distinct glycoprotein spikes, hemagluttinin antigen (HA) and neuraminidase antigen (NA). HA allows the virus to attach to host respiratory epithelium and NA is necessary for the production of new virions within a host. These factors, which are coded for by different genes in the virus’s segmented RNA, are variable, ever-mutating and responsible for the continuous spread of disease. Flu vaccines are made for type A and B viruses, with type A usually having more severe presentation. Initially more type B cases were observed this season, but the proportion of reported type A viruses is steadily increasing. Type A viruses are able to present in a range of species which increases their virulence. Whole RNA segments between species specific viruses are able to combine within an envelope and form an unrecognizable influenza variant, which is when pandemics (such as H1N1 in 2009) are usually observed.

All vaccines this season contain an updated version of hemagluttinin from the H1N1, H3N2, and 1-2 strains of type B viruses. The vaccine was 47% effective in the 2018-2019 season and is currently showing a range of 40-60% for this season. Despite reported effectiveness, receiving the vaccine confers some protection against all influenza infections even if the transmitted virus’s genome has mutated beyond the limits of the constructed vaccine. With the goal of preventing death tolls from climbing, it is important for all people to get the vaccine because even a slight immunological memory can decrease illness severity. Since children often have the highest attack rates of influenza virus, and are a key step in the widespread transmission of disease to households and at-risk communities, routine yearly vaccinations are especially encouraged. This survey uncovers some population wide misconceptions and excuses for not getting the flu vaccine. The most prevalent reasons include “forgetting” and not understanding the severity of the disease. It is not too late to receive the vaccine, participate in the yearly fight, and contribute to reducing influenza impact.

As of late December, 2019-nCoV emerged as the 3rd novel coronavirus in the past two decades, according to the New England Journal of Medicine. The CDC identifies it as the 7th known coronavirus, although there are likely more. The severe acute respiratory syndrome coronavirus (SARS-CoV) of 2003 and Middle East respiratory syndrome (MERS-CoV) of 2012 imparted case fatality rates of 9.5% and 34.4% respectively. All three are zoonotic viruses, having animal reservoirs of disease. Elimination of outbreaks depends on ability to eradicate the virus from the human population and immediate animal reservoirs. SARS has been effectively contained, while MERS outbreaks from zoonotic spillover are still a threat. There is especially high risks for transmission of these diseases in health care settings. Nosocomial transmission, or hospital-acquired viruses, accounted for 58% of SARS and 70% OF MERS cases, where many immune compromised individuals are in close contact. These statistics will help guide epidemiologist and health professionals in how to best handle the current spread of 2019-nCoV.

Shown above, viruses of the Coronaviridae family are named for their crown-like appearance. Protein spikes extend from these viruses’ envelopes in a uniform fashion, contributing to their specific actions in the respiratory tract. The genetic information contained inside the virus envelope is positive sense, non-segmented, single stranded RNA ranging from 26-32 kilobases (Kb) in size, which is large for an RNA virus. RNA viruses are much more susceptible to mutability because of the more frequent mistakes made by its RNA-dependent RNA polymerase (RDRP) during genomic replication. Accumulation of mutations results in antigenic drift and contributes to virulence. With this ability to rapidly mutate, CoVs have found a variety of mammal hosts and increasing opportunity to infect human populations.

Phylogenetic analysis (left) of this novel coronavirus suggests it originated in bats, similar to the SARS coronavirus. However, the disease was pinpointed to stem from a seafood wholesale market in Wuhan, China when many workers and visitors of the location fell ill with fever, cough, and shortness of breath. Because bats are not sold here, the animal serving as the transmission vehicle has not yet been identified. Protein analyses were additionally carried out, specifically for the aforementioned spike (S) proteins which control the virus’s point of entry into host systems. This paper showed that the receptor binding domain of the 2019-nCoV S proteins had lower affinity for the expected angiotensin converting enzyme 2 receptor (ACE2) than the related SARS virus, which could confer reduced virulence. However, the recent spike in confirmed cases, indicating effective human-to-human transmission, leads these researchers to suggest that the novel virus may be actively evolving between human hosts or has a different receiving host protein. Constant monitoring and research is necessary to determine exactly how this new coronavirus is acting in the respiratory tract and how it can be prevented.

Questions left to answer:

• Are asymptomatic individuals able to infect others?
• How long is the virus’s incubation period?
• Can existing drugs compromise any of the virus’s polymerases or proteases, thus inhibiting infection severity?
• Which animal directly transmitted the virus, and how can this reservoir be contained?
  

There are parallels between science and law. Both lawyers and scientists need a strong body of evidence to put forth a convincing novel argument. To quote Elle Woods, “you need…a reason to believe your claim should have, like, evidentiary support.”

So what happened in the case of Andrew Wakefield? Almost 22 years ago to date, Wakefield’s study (now retracted) that linked the MMR (measles, mumps, and rubella) vaccine to autism was published in the The Lancet, a top peer-reviewed medical journal. The paper discussed a cohort of 12 children. The paper claims that the subjects were “referred to the department of paediatric gastroenterology.” However, when Brian Deer followed up with the families in the midst of the article’s discrediting, he uncovered that some sought out Wakefield’s study with the undisclosed goal of suing vaccine manufacturers. It turns out that Wakefield was being funneled money to prove that his previously noted bowel-brain syndrome was associated with vaccine product-liability. He was also promoting, and in the process of patenting, his own single-virus shots that would alleviate the purported concerns with the attenuated MMR vaccine. In his investigation, Deer also illuminates many falsities included as evidence for the claim including erroneous autism diagnoses and misreported onset of symptoms post-vaccination.

In short, Wakefield’s study did not constitute sound science. The cohort was small, self-referred, free of control groups, and almost all evidentiary support stemmed from contorted parental anecdotes. Researchers behind this paper did not even attempt to replicate their findings in another context or larger sample size. Although the original paper does not assert that an association between the MMR vaccine and autism was proven, it concludes in the final sentences: “In most cases, onset of symptoms was after measles, mumps, and rubella immunisation. Further investigations are needed to examine this syndrome and its possible relation to this vaccine.” Despite the unsound science, this sentence was enough to send vulnerable parents and the ever-eager media into a frenzy. Even with the claims debunked by numerous large scale studies (1, 2, 3) , Wakefield refuses to retract his research, unlike his original colleagues, and fuels anti-vaxxer groups around the world.

Vox news openly blames journalists for propelling undeserving scientific anomalies into the public eye. The ramifications of Wakefield’s biased case-study continue to play out in current time. Although the CDC reports for 2019 that 91.5%, and 91.0% of children aged 19-35 months in the U.S. received the MMR and varicella vaccines respectively, there are significant vaccination gaps in developing countries and select groups in the developed world. Unexpected outbreaks can therefore occur when a vaccinated traveler returns to the U.S and exposes a non-vaccinated group to the disease. U.S. outbreaks are small compared to the disease incidence that occurs in areas with large immunization gaps worldwide. The World Health Organization recently reported on the 2019 reemergence of measles in the Pacific. The governments of Samoa, Tonga, and Fiji conducted effective vaccination campaigns in response to the tragic loss of life in infants and young children. Sustained investments in public health efforts, with a focus on the poorest communities, are needed worldwide. The CDC lists their efforts in the matter here.

Educating people on the effectiveness and safeness of immunizations is one of the first steps in eradicating preventable disease. Andrew Wakefield and his faulty science set back the developed world. The majority of the U.S population cannot fathom the severity associated with the measles, mumps, rubella, and varicella-zoster (chickenpox) viruses. Letting these infectious agents weasel their way back into societies where they should no longer be present is a top public health concern. Do your research, find the evidentiary support, and follow the science.

In the coming weeks, this blog will explore various topics in medical microbiology. I am a student in the Biology department at the University of North Carolina, Chapel Hill. In August, I will begin my graduate career at UNC’s Eshelman School of Pharmacy. Wrightsville Beach, NC is my favorite place to be, and I love to spend time relaxing, painting, and exploring there with friends and family! I am excited to learn about the various ways that microbiota contribute to everyday life and disease states. Educating others about the fascinating organisms that live in, on, and around us can elevate the future of clinical care!