Letter to editor

Preclinical toxicology considerations for vaccines

Reynaldo Oliva-Hernández^{1  *} 

¹Instituto Finlay de Vacunas. La Habana, Cuba.

Regarding the article published in the journal Vaccimonitor, volume 28 number 1 of the year 2019, where the results of the toxicological study carried out on the meningococcal vaccine VA-MENGOC-BC® are presented after 24 and 36 months of storage in 4 to 8°C. I would like to issue a list of considerations on some of the parameters generally evaluated in vaccine toxicology studies, in order to optimize the results that can be achieved. In this sense, we could contribute to a better design of preclinical toxicology studies in order to reach a predictive value closer to what is expected in posterior clinical trials. Similarly, these considerations can be taken into account for the analysis of ethical aspects, animal welfare and determination of the humanitarian endpoint.

Preclinical vaccine toxicology studies have become mandatory since the last decade of the 20th century, where different studies have been proposed and designed to meet these requirements. We can mention, for example, pharmacological safety studies, single dose, local tolerance and repeated dose, amongst others.¹ In each of them there are parameters to be evaluated, such as the clinical observation of the animals, body weight, water and food consumption, and the local and systemic response. However, the information that we could obtain from these parameters from the “proof of concept” studies to the toxicological studies themselves, is not exploited to the maximum.

Nowadays, the guides issued by the WHO, in my opinion, are one of the most complete, because they collect a large part of the regulations and guidelines issued by other entities such as the FDA, EMA, OECD, ICH, amongst others. They contemplate a large number of parameters to be investigated in toxicological studies, ranging from in vitro to in vivo tests.¹ On the latter, increasingly, and for good, aspects of animal welfare and the principle of 3Rs are taken into account.^1,2 In this sense, we consider that elements that could enhance the responses of some of the parameters investigated can be introduced. In our case, we designed them to provide new elements to the safety of a product with years of application, both in children and adults, without reporting serious adverse effects and with recognized safety.³

¿How can we demonstrate that a vaccine remains safe, after being kept for 36 months under controlled conditions and shows no changes in the analytical studies carried out? Also, is a repeated dose study justified?

One of the parameters in toxicological studies that should be considered mandatory and permanent is body weight. This is so because it has been considered in a wide range of toxicological studies for being a sensitive and general indicator of drug toxicity. The effects on weight usually manifest themselves as a decrease in weight gain compared to controls to absolute body weight loss, depending on the toxicity of the product tested. Body weight is a very important element and can be related to the parameters of water and food consumption and even to haematological studies, serum chemistry and anatomo-pathological findings. This is a variable where the implementation of the humanitarian endpoint must be analyzed and defined. In this regard, the upper limits for weight loss in a short period of time have already been proposed by institutions such as FELASA (Federation of European Laboratory Animal Science Associations) and other authors.^4,5

In Phase 0 and I clinical trials (safety and reactogenicity studies), some of the parameters and variables evaluated are the body temperature and the local response at the injection site, regardless of the possible systemic responses to a certain product. Animal temperature in preclinical toxicology studies may predictively contribute to the reactogenicity of a drug or vaccine in clinical trials; for that reason, it must be a parameter that needs to be incorporated permanently. Moreover, temperature is a variable that can be related to the route of administration and pain scale.⁶

It is known that a group of vaccines considered to be safe and used today have multiple undesirable adverse events in clinical trials, such as febrile states, malaise, headache or discomfort at the administration site.^7,8 These events are taken into account for risk-benefit analysis in both drug and vaccine studies.

Not many vaccines cause local inflammation, pain or other symptoms. Therefore, the exhaustive investigation of the local response of a certain product also has great predictive value for clinical trials. In this regard, we consider that the evaluation of muscle volume at the vaccine administration site using the intramuscular route allows to discern measurable local inflammatory processes; and in a consistent way when using tools of recognized precision such as Callipers. Similarly, there are other methods of evaluating local responses, such as the modified Draize method.^1,9 Despite that it is a method of lower precision, it was used for decades for in vivo dermal and ophthalmic irritability studies. Although nowadays, these studies have been replaced by in vitro tests on the base of animal welfare and the 3Rs principle fulfillment,¹⁰ we consider the Draize method useful for vaccines that use the parenteral route as a local response evaluation method. This method could provide new elements to take into account, in addition to local inflammation, the lecture of the skin throughout the injection site.

For a product such as the meningococcal VA-MENGOC-BC® vaccine, a repeat dose study in our opinion is not justified. First, because there is no history of this type for vaccines with stability and long life like this. Secondly, there is no regulation that requires these studies, in addition to the rigorous analytical tests that are carried out to demonstrate the stability of the product. Third, the repeated dose studies are not short, and besides being expensive, more animals are used, and the timing of result analyses of all the variables in an integrated manner is higher. It was mainly, by these criteria, that we designed the study of local tolerance with a single dose, taking as animal welfare philosophies, the principle of 3Rs and the analysis "case by case".¹ Hence, we finally consider that the most frequently used parameters can include others such as body temperature, musculometry (local inflammation), the Draize method, and pain assessment (by the pain scale), amongst others.

These considerations, mentioned above, suggest us to introduce in the preclinical toxicological studies as many parameters as possible with a logical rationality. Together, they may have a potential predictive value of safety for vaccines before and during clinical trials.

Referencias

1.  World Health Organization. Guidelines on the evaluation of vaccine adjuvants and adjuvanted vaccine, Technical Report Series No 987, Annex 2. Geneva: WHO; 2013. Disponible en: http://www.who.int/biologicals/vaccines/nonclinial_evaluation_of_vaccines/en/.1.

2.  Morton DB. Humane endpoints in animal experimentation for biomedical research: ethical, legal and practical aspect. Lab Anim. 2005;8:5-12.

3.  Ochoa RF, Sierra G, Martínez I, Cuevas I. Prevención de la Enfermedad Meningocócica. Ciudad de La Habana: Finlay Ediciones; 2010.

4.  Baumans V, Brain PF, Brugére H, Clausing P, Jeneskog T, Perretta G. Pain and distress in laboratory rodents and lagomorphs. Report of the Federation of European Laboratory Animal Science Associations (FELASA) Working Group on Pain and Distress accepted by the FELASA Board of Management November 1992. Lab Anim. 1994;28(2):97-112.

5.  Chapman K, Sewell F, Allais L, Delongeas JL, Donald E, Festaq M, et al. A global pharmaceutical company initiative: An evidence-based approach to define the upper limit of body weight loss in short term toxicity studies. Regul Toxicol Pharmacol 2013;67(1):27-38.

6.  Matsumiya LC, Sorge RE, Sotocinal SG, Tabaka JM, Wieskopf JS, Zaloum A, et al. Using the Mouse Grimace Scale to Reevaluate the Efficacy of Postoperative Analgesics in Laboratory Mice. J Am Assoc Lab Anim Sci. 2012;51(1):42-9.

7.  CDC, Center for Disease Control and Prevention. Flu Vaccine Safety Information. Atlanta: CDC; 2017. Disponible en: https://www.cdc.gov/flu/protect/vaccine/general.htm.7.

8.  Nichol KL, Margolis KL, Lind A, Murdoch M, McFadden R, Hauge M, et al. Side Effects Associated With Influenza Vaccination in Healthy Working Adults A Randomized, Placebo-Controlled Trial. Arch Intern Med. 1996;156(14):1546-50.

9.  Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther 1944;4(82):377-90.

10.  Organization for Economic Cooperation and Development. Test No 439, In Vitro Skin Irritation, Reconstructed Human Epidermis Test Method. Paris: OECD Publishing; 2015. Disponible en: http://dx.doi.org/10.1787/9789264242845-en.10.

Received: February 18, 2019; Accepted: April 01, 2019

^*Autor para correspondencia: [e-mail]; [e-mail]

* Médico Veterinario y Zootecnista, Master en Medicina Preventiva Veterinaria, Doctor en Ciencias de la Salud. Jefe del Departamento de Modelos Animales y Toxicología Experimental. Profesor Adjunto de la Universidad Agraria de la Habana.