Evaluating the effectiveness of mastitis vaccines and the current status of vaccine development

One of the ways to lower the incidence of mastitis in cows is to vaccinate. However, although used by some dairy farmers across the globe, this is not a method often used due to a number of reasons including ignorance and a lack of effective vaccines. Research efforts on vaccination are increasing and therefore I have consulted the literature to establish the current status. Two reviews proved to be valuable: one by Pamela Ruegg of the University of Wisconsin on Evaluating the Effectivenessof Mastitis Vaccines, published in Milk Money, Volume 3 of 2005, pages 21 to 28, and the other one by JullyGogoi Kiwari and co-workers on Trends In Therapeutic and Prevention Strategies for Management of Bovine Mastitis: An Overview, published in Vaccines & Vaccination, Volume 4 of 2013 • Issue 2 • 1000176, which is an open access journal. I have also received valuable comments on SA work from Dr Inge-Marie Petzer of UP, Onderstepoort.

Mastitis control is based upon adoption of preventative control strategies including good milking hygiene, the use of properly functioning milking equipment, provision of clean and dry housing areas, sound nutritional programs and proper identification, and (antibiotic) treatment of cows that are infected with subclinical and clinical mastitis. As far as vaccination is concerned, several efforts have been made to develop a vaccine against mastitis, but few have claimed satisfactory outcomes. It is also unlikely that a single vaccine will prevent mastitis caused by the many pathogens and their different mechanisms of pathogenesis. According to pathogenesis, mastitis organisms can be divided in four major groups which accordingly require separate vaccine approaches. These are: Staphylococcus aureus, coliforms (E. coli, Klebsiella spp.), the environmental Streptococcus uberis and other Streptococcus spp (S. agalactiae and S. dysgalactiae). Apart from the different pathogenesis, why is the development of effective vaccines against mastitis difficult, compared to other diseases? This is due to a particular uniqueness:

Mastitis is defined as inflammation of the mammary gland, yet the purpose of vaccination is to enhance the immune response. In the case of mastitis, an enhanced immune response is not always considered beneficial. One component of the immune response is the migration of large numbers of white blood cells (in the udder called somatic cells) to the infected gland. The presence of somatic cells in the milk is not considered a positive outcome as somatic cells are evidence of mastitis and reduced milk quality. Effective immunization is difficult because of the very nature of milk. The volume of milk present in the gland dilutes the number of immune cells available to fight infection and milk components such as fat and casein reduce the bactericidal abilities of the infection-fighting immune cells. Additionally, as discussed above, the cow is exposed to numerous organisms that have the potential to cause mastitis and, furthermore, milk is an excellent substrate for bacterial growth.

One of the most frustrating and also most numerous mastitis pathogens is Staphylococcus aureus. This organism is a highly successful mastitis pathogen in that it has evolved to produce infections of long duration with limited clinical signs. Most infections are subclinical and are detected by the production of poor quality milk. While clinical mastitis may occur sporadically, affected animals rarely become seriously ill and the major economic effect is reduced milk yield, discarded milk or quality premiums received by the producer. Cows are at risk throughout lactation and are often becoming infected after prolonged periods of exposure. Unless a vaccine can prevent new infections throughout lactation and dramatically reduce the somatic cell count (SCC) of affected animals, it may be difficult for a farmer to recognize the benefit of using a Staph. aureus vaccine.

The current status of vaccine efficacy against Staph. aureus is inconsistent if not confusing. Commercially available vaccines have limited ability to prevent new infections but do enhance spontaneous cure rates. The failure to prevent new infections is probably the reason why these vaccines are used on a limited basis in Staph. aureus mastitis control programs. There have also been several approaches to the development of experimental vaccines for the control of Staph. aureus mastitis: Researchers have attempted to develop vaccines directed towards specific virulence factors responsible for the development of mastitis. Vaccines have also been formulated based on bacterial cell wall components, adhesion factors and so-called Staph. aureus pseudocapsules. Results show that these vaccines normally do not reduce SCC or increase milk yields of infected cows. However, response differences are seen between herds: In some herds with a high prevalence of Staph. aureus mastitis, the vaccinated animals had a reduction in signs of clinical mastitis and reduced development of new subclinical mastitis infections. In general, there seems to be progress in the development of effective vaccines but the efficacy seems to vary by herd. The most profound effect of Staph. aureus vaccines appears to be a decrease in the development of clinical symptoms and preventive management programs are needed to effectively reduce new infections.

Coliforms (E. coli, Klebsiella sp.) are etiological agents of environmental mastitis. Mastitis caused by them is usually of short duration and less than 15% of affected animals usually develop chronic infections. Coliform mastitis is generally clinical in nature and many affected animals exhibit systemic signs of disease. The clinical symptoms associated with coliform infections are the result of toxins released from the cell wall of dying gram-negative bacteria. There is rarely a long-term impact of coliform infections on SCC. Losses attributable to coliform mastitis are associated with the clinical episode and are the result of reduced milk yield, discarded milk, treatment costs, death and culling. The highest risk period for coliform mastitis is during the immediate post-calving period. Therefore, a vaccine could be effective if it successfully reduces symptoms of coliform mastitis during this specific risk period.

 Coliform vaccines (“J5 vaccines”) have become standard practice on many dairy farms in some countries. The efficacy of these vaccines has been demonstrated in both experimental challenge trials and in field trials in commercial dairy herds. The biological principle is based upon their ability to stimulate production of antibodies directed against common core antigens that these organisms share. The vaccines are considered effective even though the rate of infection in the udder is not significantly reduced in vaccinated animals because they reduce the clinical effects of the infection. Experimental challenge studies have demonstrated that J5 vaccines are able to reduce bacterial counts in milk and result in fewer clinical symptoms. The prevailing theory is that J5 vaccines enhance the ability of white blood cells to destroy the bacteria.

Streptococcus infections are more recent concerns than coliforms and Staph. aureus. The increased frequency of mastitis caused by these species has resulted in a number of attempts to produce vaccines. There has been a sustained, focused research effort for vaccines directed against Streptococcus. uberis.  In one prominent study, repeated immunization with a killed S. uberis vaccine was effective in reducing the number of bacteria in milk from animals that were experimentally challenged with the same strain of the species. However, immunization did not reduce the SCC level. In another study, one strain each of S. uberis and S. agalactia were included in an experimental killed mastitis bacterin that was tested in a field trial. This vaccine had no significant effect on the occurrence of mastitis caused by Streptococcus organisms but the study apparently was not designed sufficiently to detect a difference if one indeed did exist. Researchers have also investigated live vaccines against S. uberis and concluded that the strain-specific nature of protection obtained would limit the applicability of live antigen vaccines.  As yet, there are no commercial vaccines available that protect against Streptococcus mastitis.

Some South African experience as communicated by Dr Inge-Marie Petzer: Her group have tested a vaccine with Spanish origin that is now registered in SA in one herd in a controlled study and they want to follow up with farm cases. This vaccine was made in a very special way and hopefully will be effective against Staph. aureus, environmental Staphylococcus (CNS), E. coli and other coliforms.

According to Dr Petzer, there are more than 120 different Staph. aureus strains that have been isolated from mastitis cases in South Africa and many are present in the same herd. So one cannot take a few Staph. aureus strains from a herd and make a vaccine against it. The specific interest in this vaccine is because the antigen is made against the biofilm that Staph. aureus forms once it is in the udder to protect it against antibiotics and lymphocytes. Studies have shown that almost 100% of the Staph. aureus and 74% of CNS isolated from milk can form biofilms. This vaccine aids to prevent the bacteria from protecting themselves resulting in less severe clinical cases, shorter duration of mastitis, better cure and lower SCC. The E coli part is the J5 strain used in many countries as discussed above, which adds further value because it also prevents severe mastitis cases and blue udder. These results are promising, some have already been published scientifically and also reported in The Dairy Mail.