VACCINE TECHNICAL REVIEWS
Technical comparison of registered veterinary vaccines
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Leptospirosis is a zoonotic disease affecting most mammalian species worldwide amongst which farm animals and pets. If the majority of Leptospira infections are either sub-clinical or result in a mild disease, a small proportion develops into a serious disease that can affect various organs (brain, hearth, spleen, liver or kidneys (Weil’s disease)) and which can be fatal. The control of leptospirosis is therefore important for both an animal and public health perspectives.
Leptospira species have been historically subdivided in serovars based on the expression of surface-exposed lipopolysaccharide (LPS). Serovars containing overlapping antigenic determinants are classified into larger serogroups. Leptospira animal vaccines have been in use for decades, whilst only a few commercial human vaccines exist1: a monovalent vaccine (Spirolet) from IMAXIO, France; a bivalent vaccine from Shanghai Institute of Biological Products and a trivalent product Vax-Spiral from the Finlay Institute in Cuba. These vaccines are used only for workers in high risk of infection. All current Leptospira human and animal health vaccines are conventionally produced and their efficacy is limited to the serovars included in their composition.
Although infection of cats is much rarer than dogs, both animals can shed Leptospira via their urine leading to potential human exposure. Canine leptospirosis is caused primarily by Leptospira interrogans and Leptospira kirschneri. The most common canine Leptospira interrogans serovars thought to infect dogs before the introduction of vaccines 50 years ago were Canicola and Icterohaemorrhagiae. It is suspected that the development and use of vaccines based on these two serovars gave rise to opportunistic infections with additional serovars in Europe such as Grippotyphosa, Australis and Sejroe2. The European canine Leptospira vaccines offer is slowly adapting in reaction to the serovar changes observed in the field with the recent introduction of new Leptospira combination vaccines. This evolution is captured in a comparison table of major canine Leptospira vaccines, built around the clinical claims agreed on the SPC (Summary of Product Characteristics) of vaccines commercially available in Europe. Although these products were registered using various routes of EU registration, their assessment was made against the same set of EU directives, guidelines and European Pharmacopoeia monographs, allowing some comparison of their clinical claims.
All canine Leptospira vaccines registered in EU contain inactivated organisms. Their safety is not a differentiation factor. Their registered efficacy claims show some differences, which could translate a difference in - the qualitative and/or quantitative composition of the Leptospira strain(s) used in the vaccine or the vaccination scheme,
- the inactivation method/duration resulting in some antigenic variations
- a positive or negative effect of an adjuvant or of a combination with multiple viral components
- the development methods (clinical trials design and/or statistical power)
- the challenge model and/or isolate used to reproduce the disease
- the interpretation between reduction and prevention claims by regulatory assessors.
EU regulators (CVMP) have tried to harmonise the efficacy claims across vaccines by adopting a position paper in 2003 on the wording of European veterinary vaccines claims (EMEA/CVMP/042/97-Rev). A concept paper was issued in 2011 to investigate the need to write a guideline to harmonise the interpretation of the reduction and prevention claims across regulatory agencies in EU and to add new claims expected from future biopharmaceutical products. This topic has not been updated since the end of consultation in December 2011 and is not on the CVMP Immunological Working Party work plan for 2015. Other canine Leptospira vaccines are available outside Europe. These were not considered for comparison as they might include serogroups with less or no relevance to European field situation. They were also registered using other sets of technical guidelines rendering the comparison meaningless.
1 Stokes, W et al (2013) Report on the international workshop on alternative methods for Leptospira vaccine potency testing. Biologicals 41, 279-294.
2 Ellis, W. A. (2010) Control of canine leptospirosis in Europe: time for a change? Veterinary Record 167, 602-605.
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MYCOPLASMA HYOPNEUMONIAE VACCINES
Mycoplasmas are members of the class Mollicutes, a group of bacteria that lack cell walls and which infect a wide variety of plants and animals, including humans. Mycoplasmas are the smallest known micro-organisms that are able to propagate in a cell-free medium. Their genomes are small. Their limited number of genes results in a lack of biosynthetic pathways leaving Mollicutes to obtain amino acids, purines, pyrimidines, and membrane components from their growth environment and making them slow and fastidious to cultivate in vitro.
Mycoplasma hyopneumoniae was first isolated in 1965 and is a micro-organism infecting only pigs. It is present worldwide and mainly associated with intensive swine production. M.hyopneumoniae infections are initiated by the colonization of the animal respiratory tract, provoking damages to the pulmonary tissue and persistence of the micro-organisms in the respiratory tract. M.hyopneumoniae, also known as enzootic pneumonia, plays a primary role in the porcine respiratory disease complex (PRDC), a leading cause of economic loss for swine producers. M.hyopneumoniae will often be the primary infection agent, helping opportunistic bacteria and viruses to establish themselves in the respiratory tract, which will increase the severity of the clinical signs and reduce the animal appetite, lowering the average daily weight gain and ultimately delaying pig's growth.
The diagnosis of enzootic pneumonia is generally made at herd level rather than at an individual level. Dry coughing is the most obvious clinical sign, although the disease can sometimes be sub-clinical. Clinical signs will be accompanied by macroscopic lung lesions which may be seen at slaughter, unless already healed in case of early infection. The clinical picture is often complicated by secondary, opportunistic infections.
In most pig herds, the highest infection levels of M.hyopneumoniae occur during the grow-finishing period, equivalent to the period between 10 and 26 weeks of age. The infection's onset and severity vary between herds and are influenced by various environmental factors such as herd management and housing conditions.
Vaccination against M.hyopneumoniae has been carried out for decades and has demonstrated that vaccines were effective in reducing the enzootic pneumonia clinical disease including percentage of lung lesions and coughing; however, vaccines do not prevent the host colonization by the micro-organism. In addition to vaccination, M.hyopneumoniae infection control includes optimization of animal management and housing practices as well as antimicrobial treatment.
Current M.hyopneumoniae vaccines available in Europe are all adjuvanted and inactivated whole-cells preparations. Their safety is not a real differentiation factor, although some formulations present more reactogenic adjuvant systems triggering larger or longer-lasting injection site reactions. These injection site reactions have however no demonstrated impact on the condemnation rate of carcasses at slaughter.
There are very few differences in the registered efficacy claims amongst these vaccines. The large majority of the vaccines provide a reduction of lung lesions sometimes defined in terms of severity and/or duration. A minority of vaccines have documented evidences of a positive effect of the vaccination on body weight or feed conversion over time compared to diseased animals.
The animal’s minimum age recommended for vaccination varies from vaccine to vaccine in function of the age of the animals used to demonstrate the safety and efficacy in the registration dossier studies. Likewise, the period between last vaccination and start of immunity (onset of immunity) and the duration of immunity vary following the data generated during clinical trials on minimum age animals. If the onset of immunity of M.hyopneumoniae monovalent vaccines varies from 3 days to 3 weeks, the duration of immunity generally covers the 26 weeks (6 months) growth period of the pigs.
The accompanying table provides a summary of the indications for use of M.hyopneumoniae monovalent and multivalent vaccines currently registered in Europe. Other M.hyopneumoniae vaccines are available outside Europe, but were not considered for comparison as they were registered using other sets of regulatory and/or technical guidelines rendering the comparison meaningless.
References and further readings:
J.D. Pollack et al, (1997). The comparative metabolism of the Mollicutes (Mycoplasmas), Crit. Rev. Microbiol.: 23 (4):269–354.
E.L. Thacker and F.C. Minion (2012). Mycoplasmosis. In: J.J. Zimmerman et al (Ed. Wiley-Blackwell): Diseases of Swine, 10th ed., 57, pp. 779- 788.
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