Immunostimulant Zelnate cleared for Canada

Animal Health: News Roundup from the September 2016 issue of Canadian Cattlemen

Bayer HealthCare Animal Health’s Zelnate DNA Immunostimulant introduced in the U.S. last fall is now approved and available in Canada.

It is the first of its kind among a new generation of products for cattle that kick-start the innate immune system when given at the time, or within 24 hours, of a disease challenge.

According to the label, Zelnate is given by intramuscular injection and indicated for use as an aid in the treatment of bovine respiratory disease (BRD) due to Mannheimia haemolytica in cattle four months of age or older.

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It is unique among immunostimulants because of its DNA technology. It is a bacterial-produced plasmid DNA surrounded by a lipid carrier. A plasmid is a tiny mol­ecule with genes that enable it to replicate on its own apart from the chromosomal DNA within a cell.

The Zelnate DNA has a pathogen-associated molecular pattern (PAMP) that causes cells of the innate immune system to treat it as an invader.

You’re not alone if your eyes glaze over when trying to decipher the language of the immune system, but Bayer’s website, innateimmunity.bayer.com, explains the process in relatively plain language from the need-to-know basics to intricate details.

In a nutshell, when a pathogen makes it past the body’s front line of defence, such as skin, sneezing and coughing, cells of the innate immune system are first on the job. These cells can’t tell one pathogen from the other. They only recognize that a micro-organism is harmful because the DNA structure of pathogens differs from the DNA structure of vertebrates.

Micro-organisms with any type of PAMP are detected by toll-like receptors (TLR) on the surfaces and inside innate immune cells. A TLR binding with a PAMP activates cells of the innate immune system setting off an orderly chain of activity that signals other cells to the danger, blocks the pathogen from multiplying, and alerts the adaptive immune system.

Dendritic cells are the go-between. They internalize the pathogen and present a tiny piece of it, called an antigen, to the adaptive immune system.

The innate immune system is fully developed at birth and provides an immediate response to a broad range of bacteria and viruses, but the cells have no memory of those pathogens and will treat each one the same way time and time again in presenting it to the adaptive immune system.

Immunostimulants help activate or increase activity of components of the innate immune system to do this job more efficiently.

The adaptive immune system has the ability to mount a deadly attack on specific pathogens that the innate immune system recognizes as foreign. When an antigen of a pathogen is presented, the T-cells of the adaptive immune system swing into action, one type attacking the pathogen directly and another producing B-cells that release antibodies that bind to the pathogen. All of the T- and B-cells generated during the response recognize the same pathogen. It can take several days or weeks for the adaptive immune system to ramp up, but the cells will immediately recognize the pathogen the next time it invades and quickly mount a strong response. This immune memory offers long-lasting protection against each specific pathogen that has gone down to defeat in the past.

The adaptive system remains dormant until the innate immune system presents an antigen, or vaccines are used to introduce antigens directly to the adaptive immune system. The person selecting the vaccine has to determine which cattle are most at risk for which diseases because the response of the adaptive immune system is specific to the antigen(s) in the vaccine. The innate immune system, on the other hand, responds to any pathogens that cattle acquire from their environment, thereby presenting those that are actual threats to the adaptive immune system.

There is a flurry of research in the pipeline testing substances that show potential to stimulate components of the innate immune system in cattle, pigs, poultry and fish. Examples include nucleic acids, bacterial cell-wall components, viral components or copies of small molecules produced by the innate immune system. Depending on the substance and the cells or activity it influences, the response could be protective or therapeutic. Some may be useful as adjuvants in vaccines to improve their efficacy.

Proving up Zelnate

According to reports on the clinical trials for licencing Zelnate in the U.S., M. haemolytica was chosen as the challenge bacteria because it is the bacteria most commonly associated with BRD. Lung lesions and mortality were used as the measures of Zelnate’s efficacy because they reflect the negative consequences of BRD. Many other studies have shown that lung lesions associated with BRD reduced average daily gain and mortality is the ultimate measure of loss.

One clinical trial tested Zelnate as a stand-alone therapy when given in the face of a BRD challenge. On day 0, steers three to four months of age were given either Zelnate or a placebo treatment by intramuscular injection and challenged intratracheally with M. haemolytica. Lung lesion scores were calculated for all calves by the end of the test on day 5. The average lung lesion score of calves in the Zelnate treatment group was 6.3 per cent of the total lung area compared to an average of 12.1 per cent of the total lung area for calves in the placebo group.

The second study tested Zelnate as a stand-alone therapy when given to calves in the face of clinical (showing signs of) BRD. This time, the calves were challenged with M. haemolytica on day 0 and 24 hours later, half the calves received the Zelnate injection and half received the placebo injection. By then, 67.5 per cent of the calves showed signs of sickness. By day 5, only 2.5 per cent of the calves that had received Zelnate had died, versus 20 per cent in the placebo group.

Field trials involving much larger groups of calves and naturally occurring BRD infections were carried out as well.

A trial comparing Zelnate to Micotil involved 2,000 calves assessed as being at medium risk for contracting BRD because they were heavier calves nearing 600 pounds, transported a short distance, but commingled from several ranches in Montana and North Dakota. On arrival, half the calves were given Zelnate and the other half received Micotil. All calves received BRD and clostridial vaccines, deworming treatment and a steroid implant. Calves pulled for BRD were treated according to the trial protocol specifying the antimicrobial to be used for the first pull and, if necessary, the second and third pulls. After that, calves that continued to show signs of BRD were considered chronic and antibiotic treatment was discontinued.

There were no statistical differences between the two treatments for sickness, re-pulls, chronics, deaths of animals pulled and treated for BRD, overall deaths due to BRD, and average daily gain.

Another field trial evaluated the performance of Zelnate alone, Draxxin alone and Draxxin+Zelnate given on arrival to 300 high-risk calves in each of the three treatment groups. All calves received BRD and clostridial vaccines along with a deworming treatment. Again, all calves pulled for BRD were treated up to three times, if needed, with antimicrobials specified in this trial’s protocol.

Draxxin provided stronger protection than Zelnate for these high-risk calves, but together they provided the best protection. Preliminary data up to 56 days after arrival show a trend toward Draxxin+Zelnate reducing sickness by 25 per cent and deaths among those treated for BRD by 50 per cent compared to Draxxin alone.

The fact sheets on all of these trials, and much more about Zelnate, are available on the Zelnate website at zelnate.com or animalhealth.bayer.ca.

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