Update: Vaccines as a tool in the post-antibiotic era

After posting the piece on vaccines yesterday, a new study by BA Diep et al was brought to my attention in which the surface proteome of a prevalent strain of MRSA was determined. Work such as this is important for identifying potential antigen combinations that could be included in future multicomponent Staphylococcus aureus vaccines.

Moreover, today the WHO published a report on antimicrobial resistance. It notes, inter alia, that

Greater emphasis should be placed on prevention, including strengthening hygiene and infection prevention and control measures, improving sanitation and access to clean water, and exploring a more widespread use of vaccines. Although preventive vaccines have become available for several bacterial infections, their application is still limited.

It's clear that a multifaceted approach is needed to deal with the antimicrobial resistance problem. The WHO study, and related commentary, helps to frame and build awareness of the issue. New vaccines could help.

(image source: WHO)

Vaccines: A tool for the post-antibiotic era?

In honor of World Immunization Week this week, I recently read two books by Paul Offit: Vaccinated: One Man's Quest to Defeat the World's Deadliest Diseases and The Cutter Incident: How America’s First Polio Vaccine Led to the Growing Vaccine Crisis. Both are excellent. Vaccinated is essentially a biography of Maurice Hilleman, but it also reviews how several of the important vaccines currently in use were developed and marketed. The Cutter Incident tells the story of incompletely inactivated lots of polio vaccine manufactured by Cutter Laboratories, which caused 40,000 cases of polio nationwide in 1955, including 200 cases of paralysis and 10 deaths. There are many pearls and much wisdom to be found in the pages of these two books; I recommend reading them.

Certainly the utility of vaccines is well demonstrated and their development and application is one of the major accomplishments of modern medicine. In the US alone the improvement of population health as vaccines have become available is remarkable. Globally, it has been estimated that vaccines prevent nearly 6 million deaths annually worldwide.

The books got me thinking about future potential vaccines. In one passage, Offit recounts the development of a pneumococcal vaccine and quotes Robert Austrian talking about the rationale for his work:

The only alternative then to protect those at high risk of early death is to prevent them from becoming ill.

This beautiful and simple idea -- a medical and public health truism if ever there was one ("an ounce of prevention is worth a pound of cure") -- strikes me as relevant to HAI and antibiotic resistant infections. Think what healthcare might be like if there were vaccines for many of the bacterial infections that are currently problematic and often resistant to antibiotics, like Staphylococcus aureus, Clostridium difficile, and Neisseria gonorrhoeae.

Several antibacterial vaccines are available, including ones for pertussis, tetanus, diphtheria, meningococcus, pneumococcus, Haemophilus influenzae type b (Hib) disease, cholera, typhoid, and anthrax. However, there are reasons that vaccines for S. aureus, C. diff, and N. gonorrhoeae (as well as others) don't yet exist. For one, the immunology can be complex, as Offit explains in the discussion of the pneumococcal vaccine. Proctor describes the situation for Staph aureus in a recent review, as do Fowler and Proctor in another review. Also, the cost of developing, testing, and licensing can be steep relative to the profits of a licensed, marketed vaccine. Yet another issue is the specter of adverse events, both real and perceived. On this point, Offit notes that

. . . a technology that would clearly save lives sits on the shelf. "We could make a group B strep vaccine tomorrow," said one senior pharmaceutical company scientist. "But it would have to be given to pregnant women and we couldn't handle the liability." 

Dempsey et al offers a recent, interesting, and partially validating study to this view of a potential group B strep (GBS) vaccine. Such issues are difficult.

That being said, perhaps vaccines should be emphasized more in the conversation regarding antibiotic resistance. I've wondered in the past about the effectiveness of developing new antibiotics when there seems to be little reason to believe, given the past track record, that they will be used responsibly. A new generation of antibiotic drugs could become useless within a few years if effective antibiotic stewardship isn't practiced globally. Vaccines, if they could be made, may offer protection against what may soon be untreatable infections. Or put differently, perhaps vaccines could be an important tool in a post-antibiotic era.

Of course, there are issues to be better understood and addressed. Recent work illustrates that Bordetella pertussis is evolving in response to the vaccine, raising the possibility that future vaccines may be associated with similar dynamics. Also, vaccines to human commensals like Staphylococcus aureus might promote overgrowth of other commensal organisms. Studies have investigated this for the case of Streptococcus vaccination and MRSA colonization and infection. Moreover, it's unclear whether people would really embrace more vaccinations given the current and recent climate surrounding vaccines.

Regardless, one seldom hears about vaccines in the conversation about antibiotic resistance. It seems like funding should address making new vaccines as well as development of new antibiotic drugs -- because Robert Austrian was right. 

(image source: CDC/PHIL)

Social media, the Manhattan Project, and big data

Social media and the Manhattan Project may seem to be completely different things, but there are facets of each that are similar. Let me explain.

The Manhattan Project was a massive and ambitious R&D project undertaken in World War II that transformed theory and data into a functioning product within a few short years. It was supported by vast resources and it brought people from many different backgrounds together to solve complex problems. Because of its success, the term "Manhattan Project" has become a cliché for any concerted effort to solve "big" problems, like energy or cancer. Although the original project was for weapons development, today the term is used in a positive light -- a project to solve an important but hard problem.

People have studied the Manhattan Project to understand why it was successful. Several factors are thought to have contributed, including:

• Talent -- the project recruited talented individuals and gave them responsibility for solving key problems.
• Youth -- the mean age of the scientific and technical staff at Los Alamos, New Mexico, where important work was done, was 25. 
• Leadership -- divisions of the project were led by people of undisputed accomplishment and they, in turn, were managed, but not micromanaged, by strong leaders.
• Focus -- the entire project was focused on outcomes and meeting milestones along the way. 
• Conviction -- participants were deeply committed to achieving the end goal before a wartime enemy did. 
• Communication -- while much of the project was protected information, free discussion within certain divisions was allowed and found to be necessary for success.   
• Dispersion -- the project had operations in several states.

Within the context of public health and medicine, social media has many of these attributes. Users tend to be young. They often organize themselves into virtual communities of interest focused on important and complex topics. Users are dispersed throughout the world and are willing to actively communicate on virtually any issue. Significant effort can be brought to bear on a question at an instant's notice. And users tend to follow online leaders and thought influencers.

Because of the number of healthcare providers and consumers using social media, and the diversity and expertise of these users, social media in medicine is an immense resource. It has been used for infectious disease surveillance; patient sentiment analysis; testing treatments and speeding patient recruitment into clinical trials; understanding views on vaccines; and many, many other purposes, too numerous to list here.

Another dimension of medical social media is the potential to produce "big data". In a previous post I discussed the need for theory and context in big data if we are to make sound inferences. Certainly, others have warned about the pitfalls of big data as well. With such social media projects comes the potential to acquire vast amounts of data in a focused, disciplined way. Social media projects hold the promise of collecting big data to address specific research questions.

I don't know if social media can be harnessed into a Manhattan Project for any single issue in healthcare, but it is clear that it is playing important roles throughout the spectrum of medicine. It is a conduit for collecting types and volumes of data previously un-imagined, for catalyzing participatory medicine and patient engagement, and for generating and sharing wisdom. The practice of medicine in the 21st Century has important psychosocial, behavioral, economic, and scientific dimensions; social media plays in them all.

(image source: David Hartley)

Measles, right here in River City

Measles used to be a major childhood disease, affecting virtually all children in dramatic periodic outbreaks. The measles virus causes high fever, rash, runny nose, conjunctivitis, and malaise. It can also result in death. In the 1960s a vaccine was developed, and it was ultimately merged into what became the currently-used MMR vaccine. That vaccine helped reduce the incidence of measles to virtually non-existent levels in the US. A recent MMWR depicts the dramatic decrease of disease after vaccine introduction:

Sadly, a 1998 report finding an association between the MMR vaccine and autism led to decrease in the incidence of vaccination and attendant increase in measles disease (inset of the graphic). That study was retracted in 2010 after investigators failed to confirm its findings. Nonetheless, a large number of consumers continue to believe the bogus result that the MMR and other vaccines cause autism and thus forgo vaccinating their children. (There are additional reasons people do not vaccinate their children besides fear of autism; just google "why I'm not vaccinating my child" and you'll get a good sampling of those reasons.)

Recent months have seen continued transmission of measles in susceptible populations across the US, including California and New York City. Why is measles a problem when an effective vaccine is so commonly available? Often, travelers become infected overseas in areas where the prevalence of the measles virus is higher than in the US, and transmit the virus to susceptible individuals (often children) when they return. In NYC, a substantial proportion of the cases appear to be in children too young for the vaccine.

The simple fact is that if people do not have immunity to measles, they are overwhelmingly likely to develop infection and disease following an exposure. This is a highly transmissible virus; estimates of the basic reproduction number, R0, are as high as 18. The high degree of herd immunity in the US limits the size of outbreaks, but, as we see in the current situations in New York and California, transmission occurs due to the presence of unvaccinated persons.

In the US, all states require children to be vaccinated before starting school. However, depending on the state, children can be exempted from the requirement for medical (notably in transplant patients and those with allergies to vaccine components), religious, or personal belief reasons. Figure 3 (shown here) of a recent MMWR on measles transmission in the US depicts the current reasons for not receiving measles vaccination. Between January and August 2013, most measles cases (82%) were in persons who were unvaccinated. Of those, 79% cited philosophical/religious objections to vaccination as the reason for not receiving the vaccine. Outbreaks related to religious communities are well documented in the news; recent examples include measles in Washington State and British Columbia, measles in New York City, and measles in Texas.

Though this post has focused measles, there are similar issues with other vaccine preventable diseases, including mumps, pertussis, meningitis, and others. Vaccine coverage, both in the US and overseas, must be increased if we are to decrease the incidence of such diseases. We must learn how to more effectively communicate the benefits and risks to those who decide against vaccination.

(image source: first graphic, Wikipedia; second & third graphics, CDC)

Travel and infection: The global mixing bowl

"Healthy travellers to countries where carbapenemases-producing Enterobacteriaceae (CPE) are endemic might be at risk for their acquisition, even without contact with the local healthcare system." So begins a recent Eurosurveillance report by Ruppé and coworkers describing acquisition of CPE by healthy travelers to India. The study describes data from the VOYAG-R project, which has many objectives, including measuring the rate of acquisition of multidrug-resistant Enterobacteriaceae (MRE) in people returning from travel Latin America, Sub-Saharan Africa, and Asia and the length of MRE carriage after trips. 

CRE was the topic of a previous blog post; such pathogens are associated with significant morbidity and mortality (especially in transplant patients and those with hematological malignancies) and are increasing in incidence globally. They are difficult to detect and treat, and are important in hospital infection prevention. The Ruppé et al study reports the acquisition of CPE in three healthy French travelers returning from India. The travelers reported no contact with hospitals or healthcare centers while traveling, leading the authors to conclude that the findings are "worrisome as they attest to the development of a community reservoir for CPE, at least in India."

The study illustrates many important issues, including that those traveling to high prevalence regions are at risk for becoming colonized with CPE. Once colonized, they can carry CPE back to their origination. One can think of such regions has having a high epidemiologic weight for the global propagation of CPE. Such movement of CPE and related pathogens has been described previously. In one example, importation of MRE strains producing NDM-1, OXA-48, and ESBL into the Netherlands after a patient received healthcare in Egypt was observed. In other cases, the acquisition of CPE cannot necessarily be attributed to travel or other risk factors, but what is clear is that such pathogens have spread over large distances and are now regularly observed in many areas. 

Other pathogens are known to exhibit transient colonization, though data are frequently rare and highly variable. The picture of latent introduction of CPE is probably also relevant for other bacteria of interest in hospital epidemiology. Such a picture highlights the need for surveillance, yes, but also for effective hospital infection prevention and control. As has been pointed out, this can be difficult, especially for CRE. We need a better understanding of the mechanical pathways of infection in order to design and implement better prevention practices. 

(image source: Wikipedia)

Raw milk, part III: The battle on the Hill

I've written previously about the raw milk movement and the dangers of consuming raw milk. Now two bills have been introduced in Congress by Rep. Thomas Massie (Republican, Kentucky). According to the Congressional Research Service, the “Milk Freedom Act of 2014”

Prohibits a federal department, agency, or court from taking any action that would prohibit, regulate, or otherwise restrict the interstate traffic of milk or a milk product that is unpasteurized and packaged for direct human consumption if such action is based solely upon a determination that because the milk or milk product is unpasteurized it is adulterated, misbranded, or otherwise in violation of federal law.

The second bill, the “Interstate Milk Freedom Act of 2014”

Prohibits a federal department, agency, or court from taking any action that would prohibit, regulate, or otherwise restrict the interstate traffic of milk or a milk product that is unpasteurized and packaged for direct human consumption if: (1) such action is based solely upon a determination that because the milk or milk product is unpasteurized it is adulterated, misbranded, or otherwise in violation of federal law; (2) the milk or milk product's state of origin allows unpasteurized milk or unpasteurized milk products to be distributed for direct human consumption by any means; (3) the milk or milk product is produced, packaged, and moved in compliance with the laws of such state of origin; and (4) the milk or milk product is moved from the state of origin for transport to another state which allows the distribution of unpasteurized milk or unpasteurized milk products for direct human consumption.

The rationale for the two bills? Personal liberty. Politico quotes Rep. Massie as saying

Today, many people are paying more attention to the food they eat, what it contains, and how it is processed. Raw milk, which has been with us for thousands of years, is making a comeback among these discerning consumers. Personal choices as basic as ‘what we feed our families’ should not be limited by the federal government. [Emphasis added.]

It's an argument that has been heard before.

It's important to understand how individuals advocating such positions evaluate the choice between the "right" to endanger themselves and those around them (e.g., children and others to whom they serve raw milk) versus the right to personal and public safety. Certainly this choice exists in other areas of human behavior and legislative decisions have been made to protect public and individual health. For example, drinking and driving is not legal. Nor is driving without a seatbelt in many states. Smoking in public places is strongly curtailed for public health and other reasons. One doesn't have the right to manufacture or possess substances like ricin that are dangerous to self and others.

Why are some more passionate about having access to potentially harmful and deadly raw milk than avoiding infections that can come from it? If you feed raw milk to a child or other individual who doesn't have the capacity or capability to evaluate the risk, isn't that unethical? I've yet to meet anyone who really embraces the prospect of E. coli associated dysentery followed by HUS and renal failure. We must do better as educators and communicate the dangers more effectively, and we must do better at listening so that we can truly understand what raw milk advocates are threatened by.

(image source: Wikimedia Commons)

Hand washing, rubbing, and posters

Every now and then one sees something that is obviously well intentioned and potentially even effective, but that is problematic nonetheless. A case in point is the poster shown at the right, proclaiming that "Alcohol-based handrubs kill bacteria more effectively than soap and water." Certainly they do, but that's not the point of handwashing with plain soap and water.

The purpose of handwashing with plain soap is to mechanically remove foreign material and microorganisms from the surface of the skin. It is not to kill microbes. Plain soaps have minimal, if any, antimicrobial activity. The purpose of alcohol-based handrubs (ABHRs) is to reduce the microbial burden on the skin to a safe level through the antimicrobial action of alcohol. Because handrubs do not remove organic material, they are not a substitute for washing visibly soiled hands. Moreover, ABHRs don't kill spore forming microorganisms such as Clostridium difficile or certain other pathogens of public health importance. Handwashing with soap and water is needed to remove such contamination. Antimicrobial soap combines the cleaning action of regular soap with antiseptic activity. 

These and related issues, such as when the different approaches are best used, are well covered by Manfred Rotter in chapter 91 of the 4th edition (2012) of the expansive text Hospital Epidemiology and Infection Control. Additional information can be found in the WHO guidelines on hand hygiene in healthcare and at a related CDC website. 

In the case of the poster above, it is available at a URL that is part of an interactive education module on hand hygiene for professional HCWs. The training itself, consistent with the poster, advises (on slide #19) that plain soaps are "good" at killing bacteria whereas ABHRs are "best" and antimicrobial soaps fall in between. I can't find evidence that plain soap kills bacteria or any other pathogen. Rather, plain soap removes pathogens by acting as a surfactant or detergent, and this seems to be well established in the literature. Perhaps "Remember to wash your hands -- Soap removes germs!" or "Alcohol-based hand rubs are often an effective alternative to soap for making your hands safe!" would have been more evidence-based, defensible, and constructive messages for a poster.

More importantly, if the overarching objective of hand hygiene -- preventing transmission of microorganisms via the hands -- is to be achieved, an awareness of the issues involved in the various approaches is needed. Knowing when to wash versus rub, and why, seems relevant to communicate widely.

(image source: CDC)