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Mission immunisation

There are many diseases that can be prevented by vaccination, but are the supply demands being met? In the light of recent closures of three government vaccine production units, Suja Nair explores ground realities

"As a socially responsible organisation and being the second largest vaccine producers in India, we are always there to come forward to meet requirements of Government of India and ensure that the EPI is implemented successfully" - Rajesh Jain Joint Managing Director Panacea Biotec

Vaccines have a vital role in preventing diseases. They are the most important and cost-effective public health interventions. Rajesh Jain, Joint Managing Director, Panacea Biotec says, “Though the Indian vaccine industry is still in its developmental stage with around Rs 1,000 crore turn over in 2006, the future seems more promising and revenues may double by 2010. Referring to a recent survey Dr Rustom Mody, Director (Quality and Research), Intas Biopharmaceuticals Limited (IBPL), says, "In comparison with US, where 15-16 different vaccines are given in childhood (three to four years), nearly seven to eight vaccines are given in India. This reflects the increasing demand for vaccines."

Supply crunch in immunisation programme

Vaccine development requires great amount of investment in R&D and high level safety and efficacy for manufacturing and developing. The role of domestic R&D and technology base in the area of vaccines is of great importance, especially in publicly funded institutions as their manufacturing cost is less and they are affordable. India is among the major makers of vaccines, with Serum Institute being the largest producer of vaccines in the world.

The public healthcare of any country depends on its immunisation programme, especially in a populated country like India. As 26 million births get added every year to India's population, demand for immunisation is also increasing.

Recently, the production facility of three vaccine producing public sector units (PSUs) under the Ministry of Health and Family Welfare were cancelled and ordered to stop production by the previous Drug Controller General (India) because they did not comply with the current Good Manufacturing Practices (cGMP) rules. Apart from these PSUs, Haffkine BioPharmaceutical was also asked to stop its manufacturing activities. Right now only the oral polio vaccines production at Haffkine is operational since it complies with the WHO requirements apart from this unit of Haffkine's all others have been stopped from producing vaccines. Ironically, they developed the first indigenous oral polio vaccine (OPV).

These enterprises were suppliers in the national immunisation programme and stopping them from producing vaccines only added to the problem of supply crunch in the programme. Haffkines institute was stopped from manufacturing vaccines because during the inspection it was observed that they were not complying with the revised Schedule 'M' of the act, a Maharashtra FDA official said. Justifying the action, the FDA official said that since the act had come into existence in 2005 the company was repeatedly asked to do the needful, but since it fell on deaf ears they had no other alternative than to stop. Further, he clarified, "We cannot allow manufacturing of any drugs or vaccines just because there is shortage in the supply. The quality of the drugs and vaccines also matter. Any drug manufacturing company has to comply with the revised Schedule 'M' requisites in order to have a valid manufacturing unit. We will not compromise on the safety, stability and efficacy of any drugs, if a given company does not comply with these, we have to stop their production foreseeing the public safety."

Jain supports this move, as he believes that government decisions are always taken keeping in mind the consumer’s health perceptive. Quality of the product is more important rather than loss of money and/or infrastructure. All said and done, though the DCGI is justifiable on the steps it has taken with respect to public safety, what is being done about the dearth of immunisation programmes. With the cancellation of production licence of these vaccines manufacturing public enterprise by the Ministry of Health and Family Healthcare, there is going to be a crunch in the supply of vaccines in the country.

Past scenario

"As of today, many private industries have invested huge amounts in vaccine R&D in India. These efforts can be further supported by making seed money available to companies at lower rate of interest or by way of some amount of subsidy/grants from the government side" - Dr Suresh S Jadhav Executive Director Serum Institute of India

There has been a concern for vaccine supply because of unanticipated shortages of routinely administered vaccines beginning in 2001. These were significant, extended shortages of vaccines against eight of the eleven vaccines—preventable childhood infectious diseases, including DTaP (diphtheria, tetanus toxoids and the acellular pertussis vaccine), MMR (measles, mumps, rubella vaccine combination varicella) and the pneumococcal conjugate vaccine. Adult tetanus and diphtheria toxoids were also in short supply. These shortages led the authoritative medical groups—the Advisory Commission on Immunisation Practices, the Academy of Paediatrics Committee on Infectious Diseases, and a similar committee of the American Academy of Family Physicians—to recommend deferral of certain immunisations and to set priorities for high-risk patients until supplies of vaccines returned to normal. But these deferrals posed an increased risk of otherwise preventable infectious diseases.

There has been a shortage in the vaccine industry from some time now. Normally, the shortages of vaccines has mainly been with reference to influenza vaccines—both seasonal flu and avian flu. The current global manufacturing capacity of flu vaccines are to the tune of 350 million doses and the concerns of the World Health Organisation (WHO) are that in case a pandemic flu strikes, theoretically all inhabitants of the world, that is a whopping 6.5 billion, would need the vaccine. However, huge efforts are being made by WHO and the vaccine manufacturers in this direction by increasing awareness at all levels, multiplying existing manufacturing capacities and adding newer capacities by other producers, as also by evaluating different routes of administration.

One hundred million doses of influenza vaccine will be available for the coming flu season, according to US government spokesperson. That's about 13 million doses more than were available last year, when the United States experienced a vaccine shortage. And for the first time ever, the Centres for Disease Control and Prevention (CDC) is planning to stockpile about 4.5 million doses for children. Because flu vaccines are tailored to each year's expected flu strain, unused doses can not be saved for the future. But the CDC does not anticipate much waste at the end of the upcoming season, despite the increase in available doses. During last year's flu season, 152 children died from the flu. Their average age was three years. About 70 percent of them had not received the vaccination. This year, the CDC has directed states to collect data on children hospitalised with influenza and to report all child deaths from flu. Apart from that there had also been BCG (Bacille Calmette-Guérin) vaccine shortage in Ireland too. This shortage came about as a result of problems with three vaccine shipments towards the back end of 2006.

Stringent rules for biological products

"Conventional vaccines use attenuated or killed forms of virus to generate antibodies in the body, but in case of a recombinant vaccine, it has only specific antigens. By isolating antigens and producing them in the laboratory, it is possible to make new vaccines that cannot transmit the virus itself" - Dr Rustom Mody Director (Quality and Research) Intas Biopharmaceuticals

Jain avers that vaccines being biological products, require lots of special measures to maintain its efficacy. A major hurdle in biosimilars is related to non- availability of clear-cut regulatory framework. All biosimilars will be assessed on a case to case basis. In the event of new regulation getting the nod from US senate, USFDA would have discretion to suggest studies to establish comparability and inter changeability. He mentions that apart from that, there are other challenges too, as drugs have to be marketed as branded products. This would create hurdles in generic prescription and substitutions, as physicians are very cautious about quality, safety and efficacy of biosimilars.

Given the Indian scenario, Jadhav says that though vaccines fall in the category of drugs, they are different. In addition, all vaccines necessarily have to pass various tests at Central Drug Laboratory, Kasauli. The recombinant vaccines have to go through the approval of review committee of genetic manipulation in the Department of Biotechnology, Ministry of Health, Government of India, and Ministry of Environment. Modi adds, "From product development, manufacture and marketing of vaccines in India, regulatory agencies including Institutional Biosafety Committee (IBSC), Review Committee on Genetic Manipulation (RCGM) and Drugs Controller General of India (DCGI) are involved at various stages."

Not just prevention but cure too

Vaccines are essentially used for preventive purpose so that from the start the body gets accustomed to the viruses and gets much needed immunity. But off late there have been lots of research and studies done where has been found that vaccines can also be used for thereauptic purposes. Currently, the disease areas where therapeutic vaccines are used or are being researched are in brain and other cancers, Human papillomavirus (HPV), HIV, Immunoglobin E (IgE) mediated allergies, leishmaniasis etc. According to an industry insider, the concept of therapeutic vaccines remains controversial, since vaccines were used for immunisation of healthy people to prevent them from getting sick. Thus, the expression 'therapeutic vaccine' is used interchangeably with biopharmaceuticals. The rationale for therapeutic vaccines for HIV is basically to restore pre-existing HIV specific immunity, to induce new CD4 and CD8 responses to HIV, to control HIV replication, to reduce the HIV viral reservoir and to blunt or delay viral rebound after set point.

Over the past decade there has been a significant change in the global vaccine market as it is very essential to curb various vaccine preventable diseases like hepatitis B, Hib, polio, influenza, dengue, Japanese encephalitis, pneumonia, rotavirus and many types of cancers. They are mainly used for preventive measures. In fact, earlier, the concept of vaccines in people's mind was that of a preventive healthcare tool only, however, vaccines are also known to have immense therapeutic value. With the advent of new cancer vaccines like HPV vaccine and many others, the therapeutic value of vaccines has been recognised by both medical fraternity and people at large. According to Mody, "Conventional vaccines use attenuated or killed forms of virus to generate antibodies in the body, but in case of a recombinant vaccine, it has only the specific antigens. By isolating antigens and producing them in the laboratory, it is possible to make new vaccines that cannot transmit the virus itself. As far as the therapeutic segment is concerned, some important viral infections like HPV, Hepatitis C virus, and Rotavirus, the scope of vaccines is immense. These vaccines work better in unknown settings."

Combination vaccines

Another way in which vaccine usage has evolved is by developing combination vaccines, by which new and effective vaccines can be evolved by combining vaccines that are already there. The paediatric combination vaccines is another important segment in the private market for prevention of five deadly diseases where one single shot is given at six, 10 and 14 weeks of life. According to Dr Suresh S Jadhav, Executive Director, Serum Institute of India, "The rationale behind developing such combination products is to reduce the number of pricks to children/infants for getting immunised by different vaccines. Additionally, these combination vaccines also require less amount of cold-storage space and even the compliance to complete the immunisation cycle is much better." He added that DPT, DPT + hepatitis B, DPT + hepatitis B + hemophilus influenza type b (Hib) + inactivated polio vaccine (IPV), MR, MMR, MMR + varicella etc are the examples of combination vaccines.

New kid on the block

Vaccine industry may definitely face shortage but companies are developing their own strategy to deal with this problem. Mody says that developing a new vaccine is not an easy job as it requires investment of both time and money. IBPL is planning to develop NDDS for proteins for nasal and mucosal delivery as an alternative to the generic injectable formulations that is currently in use. This area has strong potential of generating IP in terms of patents and publications and could provide a novel platform for delivery of many of the protein therapeutics. IBPL also announced launch of new sales divisions across India to focus on the company's product basket cater to solid tumours, haematology and supportive therapies.

Recently, Serum developed the first liquid human diploid cell rabies vaccine, which is in absorbed form and can be used immediately. In case of other tissue culture rabies vaccines, which are only available in the lyophilised form, need to be reconstituted before immunisation which sometimes can result in use of wrong diluents, accidental contamination, and therefore, ready to use liquid vaccine is always preferable. Apart from this the company is also developing meningococcal A conjugate vaccine which is a joint collaboration with Program for Appropriate Technology in Health (PATH), World Health Organisation (WHO) and Centre for Biologics Evaluation and Research (CBER),USA, informs Jadhav. This vaccine is specifically developed for the children in sub-Saharan African belt where meningococcal A is highly prevalent and endemic. This vaccine has already completed phase II clinical trials and is currently undergoing phase III trials in India. He adds, "In addition to this, we are also developing seasonal influenza, pandemic influenza and aerosol measles vaccines under a project with WHO. We are also working on the development of Rotavirus vaccine using a technology obtained from National Institutes of Health (NIH), USA."

Jain says that in order to maximise the coverage of vaccines under the Expanded Program on Immunisation (EPI), Panacea has partnered with WHO and UNICEF for more than a decade. He said, "As a socially responsible organisation and being the second largest vaccine producer in India, we are always there to come forward in meeting requirements of Government of India and ensure that the EPI is implemented successfully." Panacea has built an innovative portfolio in combination vaccines under 'easy' range of vaccines. They have been playing an imperative role in immunisation through the world's first, fully liquid combination vaccines with brands such as, 'Easy Four' and 'Easy Five', for over three years now.

There are several other projects in different stages of development and are also targeting number of new vaccines to come out in next few years. Their thermostable vaccines promise to offer real breakthrough advancement in terms of global transportation of vaccines.

Need of the hour

Many countries including the US do not have regulatory guidelines and procedures in place for approval of biosimilars. Europe has shown a degree of flexibility in its approval of five biosimilars till date. Although guidance has been issued, biosimilar developers are urged to communicate with the EMEA as approval remains on a case-by case basis. Naming of biosimilars remains a contentious and unresolved issue as it carries implications for substitution with biosimilars. The problem of vaccine crunch can always come back, hence, what we need to have is a strong back up plan. In the US The National Vaccines Advisory Committee working group considered six strategies for strengthening the vaccine supply like increasing financial incentives for research, development, production, and administration, streamlining regulatory processes, establishing government-directed programs, using vaccine stockpiles, effectively managing liability issues and enhancing communication and collaboration among key stakeholders. What we need to have is also a strong foolproof plan and government initiative to deal with the immunisation programme.

The vaccines development activity should be India-centric for diseases that are more prevalent in India and more investment and research should be done on multivalent childhood vaccines for increasing disease coverage. "As of today, many private industries have invested huge amounts in vaccine R&D in India. These efforts can be further supported by making the seed money available to the companies at lower rate of interest or by way of some amount of subsidy/grants from the government side," concludes Jadhav.

suja.nair@expressindia.com