The menace of Infectious diseases

Infectious diseases are a menace we must contain, eliminate or eradicate for survival. Dr Krishna Ella, chairman and managing director, Bharat Biotech International, Dr GVJA Harshavardhan, director, Rota Virus Vaccine Development Project, Bharat Biotech International and Dr Nagendra R Hegde, group leader, Ella Foundation propose that vaccines can play a very important role towards this goal

With an increased awareness that prevention is better than cure, focus on vaccine development and vaccination has increased. Giving us a peek into new approaches in vaccine research, also speak of the very real possibility of neglected or emerging diseases of one area becoming the global diseases of tomorrow.

Infectious diseases are responsible for death and disability. Whereas death affects us directly, disability, whether it is physical or physiological, leads to loss of labour, productivity and livelihood, not to mention the economic burden to individuals as well as to healthcare systems. The development of antibiotics, therapeutics and other pharmaceuticals in the last century has been instrumental in the control, and in some instances, the elimination of infectious diseases, especially those of bacterial origin. However, the difficulty in inhibiting obligate intracellular pathogens like viruses and some protozoa and bacteria, the emergence of drug-resistant microorganisms and the re-emergence of old scourges has raised alarm bells in developed countries. In addition, chronic diseases have either been ignored for a long time or are proving tough nuts to crack. On the other hand, poor hygiene and sanitation in underdeveloped and developing nations have never erased the burden of infectious diseases in these parts of the globe. In this context, globalisation has added yet another dimension to the spread of infectious diseases and today’s local or regional diseases could be tomorrow’s global diseases, as highlighted by AIDS, influenza, SARS, tuberculosis etc.

In countries like India where over half the population is agrarian, both deadly and disabling diseases seriously affect productivity. This is compounded by the fact that the joint family structure is a thing of the past. Nuclear families with fewer children are the norm these days, which means the whole family needs to keep healthy in order to sustain. In such a scenario, there is an increased awareness that prevention is better than cure. Therefore, never before has there been so much focus and attention on vaccine development and vaccination.

Realignment of strategies

Market scenarios for vaccines have always lagged far behind that of pharmaceuticals. The vaccine market can be categorised into high value – low volume or low value – high volume markets. Western countries, which are high value – low volume markets, were able to control several acute infectious diseases by vaccination or simply through public health measures. There is thus intense scrutiny of lifestyle diseases in those countries. Hence, demands for vaccines in developed countries are starkly different from those of developing and poor countries, where the market is high volume – low value.

Rapid spread of infectious diseases and given the sheer size of the population in Asian, African and South American countries as well as growing corporate social responsibility have brought about a realignment of strategies by vaccine manufacturers. Market strategies today are now dictated by global demand much more than local demands. The demand and supply equations are, however, dictated by the wealth of the citizens of a nation, the availability of affordable healthcare as well as national immunisation programmes. In general, poor countries depend on government schemes while developing countries like India follow mostly universal but also independent programmes of vaccination.

Avenues for vaccine research

The major classes of vaccines are killed, live attenuated, subunit and DNA vaccines. Killed vaccines though the safest class it cannot stimulate the complete array of immune response that a live vaccine elicits. Neither are the responses long-lasting or relevant in some cases (e.g., mucosal immunity). Recombinant or synthetic antigens, on the other hand, are generally far less immunogenic than killed vaccines. This has, however, been obviated in some cases by using particles which mimic the structure of the whole organism (e.g., virus-like particle). DNA vaccines have proved to be very good in laboratory animal models but not somuch in large animals or humans. Live vaccines, by contrast, stimulate very good immune responses, but are not the most sought after due to the potential danger of causing disease themselves.

There is flurry of activity in vaccine research to explore possibilities of generating genetically modified live attenuated vaccines. Various approaches include deletion of virulence determinants, construction of organisms which replicate but are unable to spread within the host, and chimeric agents containing genome of two related organisms. These are being hastened by the tremendous enhancement of our knowledge of the genetic content of various pathogens, enabling the identification of virulence factors and genes that are essential for survival of pathogens.

Other approaches have included expression of antigenic proteins through viral and bacterial vectors, display of antigenic regions on virus-like particles or phages or even viruses, and production of transgenic plants. Whatever the technology, elicitation of immune responses to vaccines is rarely robust without using adjuvants which potentiate the immunogenicity of vaccine antigens. Indeed, adjuvants may be more crucial than antigens themselves, and the unavailability of potent adjuvants may have been the major reason for the miserable failure of hundreds of proposed protein and peptide vaccines.

With few exceptions, alum remains the sole adjuvant approved for human use in majority of the countries. Although alum is able to induce a good antibody response, it has little capacity to stimulate cellular immune responses which are vitally important for robust and long-standing protection against many pathogens, especially those that are intracellular. Further, alum has the potential to cause severe local and systemic side-effects. Consequently, there is a major requirement to develop safer, non-toxic and more effective adjuvants. On the other hand, the details of how even the known adjuvants act in potentiating immune responses need to be well understood.

Importance of delivery systems

Besides adjuvants, the importance of delivery systems to vaccination can not be ignored. Administration of vaccines is accomplished by injection into the subcutis or muscles. The necessity to elicit mucosal immune responses, especially in the case of respiratory pathogens, has led to the development of nasal sprays. However, such examples are only a handful. There is intense research on the development of dermal-based delivery systems which utilise various physical, chemical or biological mechanisms. The most promising of these are the projectile- and the microneedle-based approaches. On the other hand, research on nanoparticles which can not only stably carry the antigens but also can be delivered into cells is picking up.

Understanding the immune response

Finally, understanding of the biology of the initial immune activation has led to targeting antigens to specific immune recognition cells. Another important point to remember is that it is increasingly becoming clear that the immune system is distinct in neonates versus adolescents versus adults versus geriatric individuals. Whereas immune system is still developing in childhood, and is under the influence of hormones in adolescents, it is on the decline during old age.

At the same time, certain diseases can only manifest in certain age groups, either due to inherent predisposing factors or due to the requirement for incubation period of the infectious agent. Because of this and other physiological reasons, vaccines of the future may need to address different populations, and vaccine formulations may need to be tweaked to serve the need of the target population.

Growing threat of neglected infectious diseases

Neglected areas abound in infectious diseases. Most of these are local or regional, especially in the tropics. Several tropical diseases were ignored for a long time until either the annual deaths reached millions or the diseases were knocking on the doors of Western countries. Several others still remain neglected as they do not cause death but lead to serious ill health or disability.

A major issue with neglected diseases is that many are transmitted through an intermediate host. Given that over two-thirds of human infectious diseases are zoonotic, the intermediate hosts are animals in many cases. The other intermediate hosts are insects. Together, import or movement of animals, and movement of insect vectors constitute a major threat to spread of diseases. Since it is difficult to control either one of these effectively, neglected or emerging diseases of one area are very likely to be global diseases tomorrow. We, therefore, need to be on guard all the time against infectious diseases.

In addition, there is dire necessity for medical and veterinary scientists to be working together in the name of public health. Several major infectious diseases have been responsible for decimating large numbers of human population across continents. These include small pox, influenza and plague. Whereas, some like small pox have been wiped out, other like polio are on the verge of being eradicated; influenza continues to plague us continuously.

On the other hand, infectious diseases during childhood kill millions annually. Diseases like hepatitis, AIDS, malaria, measles, pertussis, tetanus, typhoid etc. are serious and life threatening. While there is no efficacious vaccine for some, others are easily vaccine preventable.

Role of vaccination

Vaccination is next only to sanitation in the prevention of infectious diseases. In fact, vaccination is the assured preventive healthcare intervention for diarrhoea in the non-availability of clean water, hygienic food and suitable housing. Vaccine is the single most important health intervention, often the only one in the backward areas.

However, there needs to be political will and public awareness to prevent infectious diseases. Simply carrying out a universal vaccination programme will not be enough. There has to be a simultaneous thrust to improve nutritional intake, literacy and waste disposal. In addition, it cannot be government policies and execution alone, but also voluntary and active participation of the citizens that will ultimately ensure our triumph in the war on infectious diseases.

Where India stands

India has been a late riser in the international vaccine market, but the availability of skilled man-power and the capacity for manufacturing and strict control measures have catapulted us into the role of a major supplier of vaccines especially to emerging countries. India also is producing new and innovative vaccines. As an example, Seth Berkeley, chief executive officer, Global Alliance for Vaccines and Immunization (GAVI) acknowledged the thrust given for the availability of Rotavirus vaccine at $.3 for three doses for infants. Even multinational companies are either setting up manufacturing facilities or tying up with local companies. This has not only raised our standards but has also pushed for changes in regulatory systems. Our manufacturing, quality control and quality assurance, and regulatory approval processes now rival international standards.

Simultaneously, we have also woken up to the complexity, duration and the cost of pre-clinical and clinical studies. Independent development of new vaccines from scratch is therefore a challenge for Indian manufacturers, and the time it takes almost makes it mandatory to be supported extensively by the Government for research, development and marketing.

International organisations such as GAVI do recommend that countries create their own database and analyse it themselves to arrive at better decisions and utilisation of resources for the introduction of improved vaccines such as the pentavalent vaccine which would be major healthcare intervention to prevent deaths of children under five years of age due to bacterial and viral infections. In this context, the role of organisations like The Bill & Melinda Gates Foundation, GAVI and the European Union cannot be ignored. Such organisations can play a pivotal role in funding promising initiatives as well as in getting the vaccines to those that need them the most, and at affordable cost.

World Health Organization and UNICEF are responsive to the requirements of the developing and emerging countries of safe, pure and efficacious vaccines and are coordinating with the vaccine manufacturers for the production of quality vaccines. GAVI believes that vaccines are democratic interventions; they work for all the in the same way. The drastic reduction in infant and child mortality in the developing and emerging countries could be achieved by adopting the adage, ‘Vaccinate as many as you can, and the most vulnerable’