Editor's note: last in a series.
Over the years several methods have been tried, with varying results, to prevent and control leptospirosis caused by serovar Hardjo-bovis in cattle. Renewed efforts are being made to identify serovars and manage the disease.
One option many veterinarians have used to clear lepto infections has been the use of long-acting tetracycline. Leptospira organisms are bacteria, so antibiotic therapy intuitively makes sense. "If we take the organisms out of the cow, they're susceptible to virtually every antibiotic made," says Carole Bolin, DVM, PhD, Diagnostic Center for Population and Animal Health, Michigan State University. "However, the issue in the cow is getting the drug levels high enough at the site of infection for long enough periods of time to solve the problem."
Bolin notes that in other countries, long-acting amoxicillin has been used successfully, but that option is not available in the United States. "So we look at multiple injections of tetracycline to maintain blood levels for a significant period of time, which becomes a real management problem." She adds that another problem is that a single, efficacious injection would be at the dose for respiratory disease (9 mg/lb) which is a large volume of drug and requires administration at multiple sites.
Bradley Mills, DVM, Rocky Creek Veterinary Services, Olin, N.C., started using antibiotics before an efficacious serovar Hardjo vaccine was available. "We gave oxytetracyline at dry-off, which is an extralabel use, but we saw a clinical response in that we cut out a lot of abortions and premature calving. We now vaccinate whole herds of cattle because we have to both clear infections and stop transmission."
Antibiotic treatment will not eradicate the disease, however. Mark Hardesty, DVM, Maria Stein Animal Clinic, Inc., Maria Stein, Ohio, at one time thought that was possible because of the excellent results he achieved with long-acting tetracycline given at dry-off. Within six months there was a positive effect on reproductive performance. "We thought we'd conquered that mountain," he says. "But a year and a half later we were back at the bottom of the mountain again and had to re-institute antibiotic therapy."
Hardesty says he's comfortable with the extra-label use of the long-acting tetracycline because he's fulfilled the requirements of the Animal Medicinal Drug Use Clarification Act (AMDUCA). "Bovine practitioners live in an exciting time where prudent, diagnosis-based drug use will supplant untargeted treatments. We've done the diagnostics and have published data from the Journal of Dairy Science that says it's effective. Plus, there are no other tools effective for clearing the infection."
Once you've aggressively attacked the Hardjo-bovis problem on an operation, every animal coming to the farm is a risk unless its status is known.
Antibiotic therapy isn't only useful in dairy herds with lepto problems; Tom Hairgrove, DVM, Dipl. ABVP, Haskell Veterinary Clinic, Haskell, Texas, has used tetracycline when he's been in a lepto wreck with beef herds. Haskell questions if it's a good idea to treat incoming heifers with tetracycline if he has a concern about Hardjo-bovis.
Bolin suggests that once you've aggressively attacked the Hardjo-bovis problem on an operation, every animal coming to the farm is a risk unless its status is known. "So treat them and vaccinate them. There's no point in doing a good job on the farm and then letting other animals come in," she says.
Acute disease vs. carrier state
Veterinarians also need to consider what it is they are trying to do when using antibiotics for leptospirosis problems in general. "You're trying to treat two different things," says Bolin. "With serovar Hardjo-bovis, you're trying to clean up long-term carriers and, in cleaning them up, deal with some of the clinical signs they may have in terms of reproduction."
With other serovars, in acutely ill calves and sick animals, the lepto organisms are dispersed in high numbers, not just localized in the kidney and reproductive tract. In the face of an abortion storm, for example, caused by serovars Pomona or Grippotyphosa, use of antibiotics can be helpful because they tend to stop the abortions. "You're not trying to clear up shedding," explains Bolin. "You're trying to treat clinical disease."
Tetracycline treatment has been tested with the carrier state. Data from overseas looked at animals infected with both types of Hardjo – Hardjo-prajitno (European) and Hardjo-bovis (worldwide). In that study, not all of the lepto was cleared from the reproductive tracts, but in all of those cases, what was left behind was Hardjo-prajitno – Hardjo-bovis was eliminated. "Nothing is 100%, but you're going to do a good job with female reproductive tracts and kidneys in carrier cows with that dose of tetracycline," says Bolin. "You could probably drop the dose down to 5mg/lb., but then I'd give a second injection at a later time."
In times of ecological stress, such as severe drought where cattle and wildlife tend to congregate near water sources or flood situations with dissemination of organisms over a large area, lepto problems can become widespread.
Immune response to lepto
It's important to understand how the immune system responds to different serovars of the disease. It appears that lepto is not immunosuppressive like BVDV. "There's an interesting dichotomy in the immune response of cattle to infection with Hardjo-bovis and to infection with other kinds of lepto," Bolin says. "In non-Hardjo-bovis infections, the antibody response is very brisk. About 10 to 14 days after infection and soon after clinical signs occur, the body starts making lots of antibody that effectively locks up the organisms in circulation and helps kill the leptospires. The animal may become sick or even die. The immune response is probably protective for the animal's life. If an animal gets Pomona and recovers, it is likely that it will never get Pomona again."
With Hardjo-bovis, it's almost the opposite. Around 80% of cows given Hardjo-bovis will seroco vert and make measurable antibodies, says Bolin. But unlike high L. Pomona titers (1600 and 3200), the titers are often 100 to 200 or less. "In most of our diagnostic testing, that's going to come back as a negative result from the lab. Even if they have a good response – an 800 titer to Hardjo-bovis after infection, for example – that antibody is quickly gone." By eight weeks after the initial infection, many Hardjo-bovis-infected cows are seronegative.
Bolin says older vaccines were designed for infections like those that are seen with Pomona. "If a vaccine induces antibodies against Pomona, the animal is protected from clinical disease. Hardjo-bovis vaccines were designed the same way, to induce antibody, but we found that the antibody that was produced after vaccination was not protective."
It turns out that vaccines that do a good job of protecting against Hardjo-bovis have common characteristics. They induce a strong cell-mediated immune (CMI) response against this organism. "There's nothing in our immunology textbooks that would suggest you need a cell-mediated immune response to protect against an extra-cellular bacterial infection like leptospirosis," explains Bolin. "You need such a response to protect against tuberculosis and many viruses, but with an extra-cellular bacteria, why would a CMI response be important? We still don't know."
Bolin has found that the vaccines that do not work against Hardjo-bovis do not induce any CMI response. "Therefore, it's intriguing to suggest that the cell-mediated response is what is required for protection against Hardjo-bovis in cattle."
She explains this with the example of a naturally infected cow that is seronegative and still shedding. She self-cures, but field experience indicates that she can get re-infected. "They have a little bit of a CMI response after infection, but it's nothing compared to what the vaccines produce, and it may not be protective. So we have a couple of lines of evidence that are leading us to believe there's something about this organism and its relationship with cows that leads to a requirement for an unusual type of immune response for protection. We have to think about Hardjo-bovis in cattle in a totally different way than we are used to. There are reasons why the current vaccines don't work against Hardjo-bovis. They were produced to do what we thought we needed for protection based on the experience with other leptospiral serovars."
For vaccines to be effective to prevent disease, they need to be given to healthy animals at appropriate times. Bolin says "adequate vaccination" in practice is sometimes tough to determine as not all vaccinations are given as scheduled, and some serovars of leptospirosis can break through vaccination. "We have some very virulent Pomona strains that can continue to cause problems in vaccinated herds. Veterinarians have trouble dealing with those cases because they tend to use even more vaccine and that may not break the cycle of transmission."
Hairgrove has seen a fair bit of Pomona in beef cattle. "Usually, it's in an area of my practice where there's a lot of irrigation," he says. "Just about every time I see a wreck, it's where they forgot to vaccinate for a while."
Bradley Mills, DVM, likes to vaccinate calves and heifers for leptospirosis before they start commingling with other animals.
Another problem Hairgrove sees with Pomona is when there is high stress or a drought situation. Bolin suggests that in times of ecological stress, wildlife are also stressed and may be sharing the same troughs and streams as cattle. "In severe drought where animals tend to congregate near water sources or the situation of a flood where you have dissemination of organisms over a large area, you're always going to have extra problems."
Bolin says there is little firm data on the duration of immunity of lepto vaccines. "People think duration is fairly short because the antibody titers disappear fairly quickly," she says. "Are they gone or are they just at a titer of less than 1:100? Is a titer of 1:99 less protective than 1:100? In some cases, we don't even know if the titer of 1:100 is protective." There's no evidence that vaccination will clear up carriers of serovar Hardjo, however. And, cows can clear themselves of a lepto infection without antibiotics. "Cows do stop shedding serovar Hardjo at some point. They stop shedding and then they may get re-infected. We don't know exactly how long it takes a cow from having just cleared an infection until she's susceptible to re-infection, but the clinical evidence is reasonably good that this does occur."
So, if a vaccine is introduced suddenly into that infected herd and there are animals that are just about ready to self-cure, the vaccine can stop them from getting re-infected, reducing the measurable infection rate in the herd with time. "Without a doubt, doing nothing but using two doses of good serovar Hardjo vaccine into the cows and calves on the farm will have a dramatic impact on the numbers of animals that are infected over a period of time," says Bolin. "In fact, you can eradicate Hardjo-bovis with a good vaccination program. It may take two years, but the New Zealand experience proves that. Over two years and starting with a high percentage of cows infected, the infection virtually disappeared." Whether those individual cows were cured by the vaccine is unknown, but Bolin adds that vaccine can dramatically decrease the prevalence of infection.
As with many diseases, however, vaccinating blind without knowing the disease status of a herd or what diseases are threatening a herd may be a waste of time and money. "I've had clients ask if they should vaccinate," Hardesty says. "I ask them if they've had a positive diagnosis. In my opinion, you just don't use the vaccine without a diagnosis."
Mike Katsampes, DVM, Milliken, Colo., has done many types of lepto vaccination protocols from once per year to four times per year. "The expense adds up when you have to vaccinate with a 5-way three or four times per year and are not getting the Hardjo-bovis protection," he says. He has even had serum from a herd on a four-times-per-year vaccination schedule test positive for lepto. But if you're not using an effective Hardjo-bovis vaccine, Bolin says it's not going to matter how often you give it if you have Hardjo-bovis in the herd. Currently, Katsampes vaccinates youngstock twice and follows with a yearly booster of the regular 5-way and uses SpirovacTM (Pfizer Animal Health) for the Hardjo-bovis fraction.
Bolin suggests concentrating on getting the two initial doses of 5-way vaccine and/or Spirovac in early, which is often a challenge for beef operations. "In relatively low-exposure situations, like the ranges of Colorado, I would give a booster vaccination once a year thereafter. The odds are this strategy will induce antibodies. For the non-Hardjo serovars, antibodies are protective. In my opinion, you don't need a high titer of antibodies to provide protection, just enough to tie the organisms up when they first get into the cow."
Mills likes to get the vaccine in calves and heifers before they start commingling with other animals, and he likes to give an annual booster to every adult animal. "In the big herds, if they're giving BST and running all the cows through the management rail once every two weeks anyway, you can give the vaccine at that time and it works well. The vaccine-associated drop in milk has been minimal, and we haven't seen reproductive problems."
Hairgrove vaccinated a well-managed beef herd with two doses per animal. This year he vaccinated them pre-breeding. These were cattle going into an AI lot. "It's too early to tell, but on first conception with AI, we got about a 10% increase this year over the last three years."
Hardesty says veterinarians and their clients need to decide how they are going to set up their vaccination protocols. He is giving two initial doses and one annual dose of Spirovac. "Are your annual vaccinations going to be that everyone gets it today or perhaps just heifers pre-breeding? Or cows at dry-off?" He is currently giving it at one month of age, two months of age, pre-breeding in the heifers and is making it a pre-calving vaccination. "I prefer pre-calving to pre-breeding because there's some discussion about peripheral mononucleocytes having a greater ability to clear lepto two months after the vaccine is in them than in the first two months."
Bolin agrees that the maximal CMI response does build somewhat over time, and the maximal response of some of the components of the immune system is perhaps out at three months. "I understand the logic of giving the vaccine pre-calving, but my only caveat would be that I never like to vaccinate pregnant cows if I have an alternative."
Katsampes says using the Hardjo-bovis vaccine helped one of his herds struggling with reproductive problems. "They had poor reproductive performance, including conception rates in the low 20s.We had not changed personnel and had thoroughly reviewed procedures and protocols. We vaccinated and boostered 8-10 weeks later." Post-vaccination he saw an increase in performance and conception rates. Pregnancy rates increased from 9-10% to 13-14%. "That sounds average, but when you're below average, that's a tremendous change."
Giving a 5-way lepto and the Hardjo-bovis vaccine may cause concern about endotoxin load, but Bolin says generally leptospiral vaccine endotoxin is pretty mild.
A lot has been learned about lepto and serovar Hardjo-bovis, but a lot more remains to be discovered. Bolin believes the Hardjo-bovis vaccine is essential for leptospirosis eradication, but she'd like research to help understand what the window of "two initial doses" means, especially in beef cattle. "Range cattle are handled maybe at branding and maybe at weaning, and those may be four to six months apart. The Hardjo-bovis vaccine label says two doses four weeks apart is the recommendation because that's how it has been tested, but does six weeks or eight weeks make a difference? What about four to six months apart? We need to define what the window of getting that second dose is in the beef cattle population."
Bolin summarizes her thoughts on how veterinarians should look at vaccinating for leptospirosis:
An ideal vaccination for every cow in the country would be to have Hardjo-bovis at the top of the list for beef or dairy. Pomona is clearly number two. "We know that probably 20-30% of the skunks and possums in any given area are infected with Pomona and perfectly willing to pass it around," says Bolin.
Grippotyphosa is number three and is carried by raccoons. "We're seeing a lot of Grippotyphosa in dogs now, and they're probably getting it from raccoons." Next is Icterohaemorrhagiae because it's common in rats. "We're doing a better job of keeping our feed stored, and our rat problems are not huge." Canicola is a pretty rare event. It can be dramatic when it happens, but Bolin doesn't think the data would support a national vaccine strategy for it.
"If we were formulating cattle lepto vaccine from scratch, I'd start with a strong Hardjo-bovis base, add a good Pomona and Grippotyphosa to that, and call it good," says Bolin.
This information is from a Bovine Veterinarian leptospirosis roundtable moderated by Mira McGregor, DVM, and sponsored by Pfizer Animal Health.
It may be wise to treat and vaccinate bulls purchased from an unknown source before they are used on the farm.
Lepto and bulls
Leptospirosis is also a disease that affects bulls. Because bulls can transmit leptospirosis through body fluids, it's critical to prevent, treat and control infections.
Bulls are commonly both vaccinated for leptospirosis and treated with antibiotics to clear the "carrier state." Bradley Mills, DVM, says he addresses the bull problem through antibiotics to clear infections and vaccinations to prevent re-infections. "There's good evidence that oxytetracycline will clear it in cows, but there's a question about curing it in bulls."
Bulls are probably harder to clear, agrees Carole Bolin, DVM, PhD. "Our diagnostics are not as good in bulls. A lot of people are using antibiotics in bull studs. They'll have bulls that get a titer to Hardjo-bovis, and they want that titer to be gone, but antibiotics are largely ineffective in making the titer decrease."
How effective the antibiotics are in actually curing the bull of the infection is a separate matter. In theory, it should work, but it may not work as well as it apparently does in cows. Bolin says the drug regimen should eliminate the infection from the kidneys, but some think that the drugs do not penetrate the tissues of the bull's reproductive tract sufficiently to have the desired effect.
"Unless you do something to change the infection dynamic in the herd, any replacement bulls are going to be quickly infected," she says. She recommends treating and vaccinating bulls purchased from an unknown source before they are used on the farm. Treatment with antibiotics and vaccination can be done at the same time.
"Introducing new vaccinated bulls would be the best, however many people have money invested, especially in purebred situations, in some very expensive, infected bulls," says Bolin. "I would vaccinate and treat those bulls."