Scientists have produced and tested, in mice, a vaccine that protects against a worrisome superbug: a hypervirulent form of the bacteria Klebsiella pneumoniae.
And they’ve done so by genetically manipulating a harmless form of E. coli, report researchers at Washington University School of Medicine in St. Louis and VaxNewMo, a St. Louis-based startup.
Klebsiella pneumoniae causes a variety of infections including rare but life-threatening liver, respiratory tract, bloodstream and other infections.
Little is known about how exactly people become infected, and the bacteria are unusually adept at acquiring resistance to antibiotics.
The prototype vaccine, details of which are published online Aug. 27 in Proceedings of the National Academy of Sciences, may offer a way to protect people against a lethal infection that is hard to prevent and treat.
“For a long time, Klebsiella was primarily an issue in the hospital setting, so even though drug resistance was a real problem in treating these infections, the impact on the public was limited,” said co-author David A. Rosen, MD, Ph.D., an assistant professor of pediatrics and of molecular microbiology at Washington University.
“But now we’re seeing Klebsiella strains that are virulent enough to cause death or severe disease in healthy people in the community.
And in the past five years, the really resistant bugs and the really virulent bugs have begun to merge so we’re beginning to see drug-resistant, hypervirulent strains. And that’s very scary.”
Hypervirulent strains of Klebsiella caused tens of thousands of infections in China, Taiwan and South Korea last year, and the bacteria are spreading around the world.
About half of people infected with hypervirulent, drug-resistant Klebsiella die. Two types in particular—known as K1 and K2—are responsible for 70 percent of the cases.
Rosen; senior author Christian Harding, Ph.D., a co-founder of VaxNewMo; first author Mario Feldman, Ph.D., an associate professor of molecular microbiology at Washington University and a co-founder of VaxNewMo; and colleagues decided to create a vaccine against the two most common strains of hypervirulent Klebsiella.
The bacterium’s outer surface is coated with sugars so the researchers designed a glycoconjugate vaccine composed of these sugars linked to a protein that helps make the vaccine more effective.
Similar vaccines have proven highly successful at protecting people against deadly diseases such as bacterial meningitis and a kind of pneumonia.
“Glycoconjugate vaccines are among the most effective, but traditionally they’ve involved a lot of chemical synthesis, which is slow and expensive,” Harding said.
“We’ve replaced chemistry with biology by engineering E. coli to do all the synthesis for us.”
The researchers genetically modified a harmless strain of E. coli, converting it into tiny biological factories capable of churning out the protein and sugars needed for the vaccine. Then they used another bacterial enzyme to link the proteins and sugars together.
To test the vaccine, the researchers gave groups of 20 mice three doses of the vaccine or a placebo at two-week intervals.
Then they challenged the mice with about 50 bacteria of either the K1 or the K2 type. Previous studies had shown that just 50 hypervirulent Klebsiella bacteria are enough to kill a mouse.
In contrast, it takes tens of millions of classical Klebsiella—the kind that affects hospitalized people—to be similarly lethal.
Of the mice that received the placebo, 80 percent infected with the K1 type and 30 percent infected with the K2 type died. In contrast, of the vaccinated mice, 80 percent infected with K1 and all of those infected with K2 survived.
“We are very happy with how effective this vaccine was,” Feldman said. “We’re working on scaling up production and optimizing the protocol so we can be ready to take the vaccine into clinical trials soon.”
The goal is to get a vaccine ready for human use before the hypervirulent strains start causing disease in even larger numbers of people.
“As a pediatrician, I want to see people get immunity to this bug as early as possible,” Rosen said. “It’s still rare in the United States, but given the high likelihood of dying or having severe debilitating disease, I think you could argue for vaccinating everybody. And soon we may not have a choice. The number of cases is increasing, and we’re going to get to the point that we’ll need to vaccinate everybody.”
K. pneumoniae is a Gram-negative bacterium found in the normal flora of the human mouth and intestine that primarily causes hospital-acquired infections, but can also cause community-acquired infections in immunocompromised patients .
Although K. pneumoniae is part of the Enterobacteriaceae family, it has been considered separately in this assessment because of its high incidence relative to other members of the Enterobacteriaceae family.
It is transmitted on medical equipment, on the hands of healthcare workers, or from environmental reservoirs .
Common clinical presentations and accompanying symptoms of K. pneumoniae infection include:
- Pneumonia: fever, cough, increased sputum production, pleuritic chest pain, dyspnoea, tachypnoea, crackles on physical examination.
- Urinary tract infection (UTI): frequency, dysuria, malaise, fever, loin pain
- Liver abscess: fever, right upper quadrant abdominal pain, chills
Less common presentations include spontaneous bacterial peritonitis, endophthalmitis, skin and soft tissue infections, and brain abscess.
Populations at greatest risk of K. pneumoniae infection are immunocompromised individuals, including those with diabetes, chronic lung conditions, HIV-positive individuals, and hospitalised patients. Patients who contract K. pneumoniae pneumonia may be on ventilator support, immunocompromised or have chronic airways disease e.g. COPD .
Those who contract K. pneumoniae UTIs may have catheters .
Hospital-acquired K. pneumoniae infections occur worldwide, but incidence of community-acquired infection varies by country.
For example, Taiwan and South Africa have higher incidence of community-acquired pneumonia caused by K. pneumonia than other countries .
Direct health impact
Global data on disease burden is not available from the IHME, WHO or in the research literature 31,32. The global burden of UTIs and lower respiratory tract infections (LRTIs) including pneumonia from all causes are available from the IHME 31. A review of the research literature suggests that K. pneumoniae is responsible for ~7% of UTIs 82 and ~4% of LRTIs 33. Given the lack of direct data on the burden of K. pneumoniae, it is challenging to assess the global burden precisely with confidence. A full methodology for this assessment can be found in the appendix.
Scoring: Based on the above analysis, mortality was categorised as medium (score of 1 out of 2) and morbidity was categorised as low (score of 0 out of 2).
A vaccine would particularly benefit immunocompromised individuals, hospitalised patients (including intensive care patients and patients with invasive devices, including urinary catheters ), the elderly, and individuals with chronic conditions (including chronic lung conditions, chronic liver disease, and dialysis patients ).
Typical antibiotic treatment courses for LRTIs and UTIs are approximately one week in duration. An international panel of experts, convened by the Infectious Diseases Society of America (IDSA) in collaboration with the European Society for Microbiology and Infectious Diseases (ESCMID), suggests nitrofurantoin is an appropriate treatment for uncomplicated UTIs .
Other appropriate treatments include trimethoprim and beta-lactam/beta-lactamase combinations .
Treatment for lower respiratory tract infection depends upon hospitalisation status and patient exposure to antibiotics. For hospitalised patients with no risk-factors for drug resistance, piperacillin-tazobactam or cefepime may be used.
Given the high incidence of UTIs, K. pneumoniae associated antibiotic use is primarily driven by UTIs.
Scoring: Based on the above analysis, antibiotic usage was categorised as medium (score of 1 out of 2). This estimate is based on an annual incidence of ~25 million UTIs and ~10 million LRTIs, both treated with a seven day course of antibiotics.
Urgency of AMR threat
Both the WHO and CDC have expressed concern about K. pneumoniae developing AMR. The WHO has listed K. pneumoniae as a member of the Enterobacteriaceae group of pathogens under the ‘critical’ priority pathogens for R&D regarding new antibiotics 6 and the CDC has listed carbapenem-resistant Enterobacteriaceae as an urgent threat in its list of biggest threats from AMR .
Extended-spectrum beta-lactamase (ESBL) resistant strains have also been listed as a serious threat on the CDC list .
Both ESBL and carbapenemase-producing Enterobacteriaceae (CPE) K. pneumoniae strains have been reported worldwide . CPE strains frequently also exhibit resistance to fluoroquinolones and aminoglycosides.
More information: Mario F. Feldman et al, A promising bioconjugate vaccine against hypervirulent Klebsiella pneumoniae, Proceedings of the National Academy of Sciences (2019). DOI: 10.1073/pnas.1907833116
Journal information: Proceedings of the National Academy of Sciences
Provided by Washington University School of Medicine