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Vaccines in India

Status of Vaccines Production in India

S. N. Jogdand

Appeared in Chemical Weekly of 5th Feb. 2002 (Not updated after that)

Introduction

Vaccination practice has a long history and prevention is better than cure is an accepted fact.  Recently there has been considerable research and progress in development of effective vaccines for most of the infectious diseases. Conventional vaccines had many limitations and certain drawbacks. With the advent of biotechnology it has become possible to develop cheaper, efficient, safer and easy to produce vaccines. Recombinant vaccines, subunit vaccines, synthetic peptides as vaccines, disabled mutants as vaccines, oral application of antigens, genetic immunization are the few examples of new approaches with certain advantages in their use. Recombinant vaccines, subunits vaccines, disabled mutants have been in use but other approaches are still mostly at research level.  

It is still true that, while the WHO expects work for the eradication of diseases, most of the biotechnology companies today are working on medical products for the cure of diseases. WHO and others adopted smallpox eradication programme in 1956. Following the impressive success of smallpox eradication, the world health organization looked for expanding the programme of immunization. Six diseases chosen were smallpox, tuberculosis, diphtheria, neonatal tetanus, whooping cough, poliomyelitis and measles. 

Vaccines used in National Immunization Programme until 1974 Vaccines used by the Expanded Programme on Immunization after 1974
  • Smallpox
  • BCG (Tuberculosis)
  • Diphtheria Toxoid
  • Tetanus Toxoid
  • Pertusis
  • IPV the OPV
  • Measles
  • BCG(Tuberculosis)
  • Diphtheria Toxoid
  • Tetanus Toxoid
  • Pertusis
  • IPV then OPV (Injectable & Oral Polio vaccine
  • Measles
  • Yellow Fever (in endemic countries)
  • Hepatitis B
  • Measles, Mumps, Rubella (MMR)
 

The WHO recently listed bacterial and amoebic dysentery, cholera, typhoid as the diseases of top priority for public health efforts. These diseases alone are responsible for 80% of illness worldwide and cause more than 20 million deaths annually.

Second in the priority are the parasite diseases such as malaria, leishmaniasis, trypanosomiasis, oulliver blindness. Together these diseases affect 1 billion people. A group of rare disorders such as rashes, leprosy, dengue fever and Japanese encephalitis are also considered as high priorities.

While most of the vaccines are for prophylactic purpose there are some vaccines like Japanese B encephalitis vaccine and Meningococcal vaccine (against Neisseria meningitis infection – meningitis and septicaemia) which are recommended during epidemics and some vaccines are meant for High Risk Groups like Pneumococcal vaccine (against Streptococcus pneumoniae infection) and Influenza Vaccine.

Newer Approaches in Vaccine Production

Understanding of the basic mechanisms of pathogenesis and body defenses is required for development of new vaccines. Knowledge of not only virulence (disease producing) genes of pathogens but also of antigen (foreign substances of pathogens) presentation, immunological memory, and of antigens and epitopes recognized by the immune system is required. The current efforts in vaccine development are mainly to improve efficacy, safety and stability of existing vaccines and to simplify the vaccination schedule.  Other attributes in mind are administration of vaccine at birth, or shortly thereafter so as to protect most vulnerable age-group children. Also heat-stable vaccines be produced if possible so that requirement of cold storage in transport can be avoided. Reducing the need of multiple doses without compromise on the protection is also one of the aims of new vaccines. Vaccination by oral route may be useful particularly in developing countries to avoid use of needles so as to limit the risk of infection by agents such as HIV1.

Thus a perfect vaccine may be a fully defined, totally synthetic, single dose and oral vaccine. While thinking of an ideal live vaccine it would be a great advantage if we have a vaccine that spreads naturally but without causing a disease. This will reduce problems in implementation of vaccination programmes. Currently used live polio vaccine spreads among contacts and helps to maintain higher level of protection in population. The objection to this concept can be from manufacturer’s viewpoint as it would be uneconomic, as once released there may not be a need again. From ethical point of view there are group of individuals who do not want to be vaccinated for religious or other reasons, which cannot be ensured. Also immunosuppressed individuals may show serious sideeffects (illness) due to natural spread of vaccine. From safety point of view the possibility of reversion of a strain to pathogenic form must be eliminated. Worldwide confidence in quality and safety is important.

Joint R&D projects for HIV, Cholera, TB and malaria and leprosy vaccines are becoming part of the new drive for Action Programmes to be jointly implemented by India and USA.

Indian corporates like Biological Evans, Serum Institute, Indian Immunologicals, Shantha Biotechnics, Bharat Biotech, Zydus Cadila, Biocon and Cadila Pharmaceuticals, Keepharma and Panacea Biotech have produced significant results in new vaccine development in the recent past. 

Joint venture projects supported by the DBT have resulted in developed DNA-based vaccines too, for diseases such as TB and rabies. Besides, a recombinant cholera vaccine strain has been patented by DBT in the US too. Recent meetings of US health department officials and senior scientists with Drug Controller and senior officials of Dept. of Biotechnology reoriented on focus of the programme to facilitate local production of DNA vaccines.

Serum Institute Of India will start active basic research with focus on new DNA vaccines and protein fragments vaccines at its inhouse R&D center. The company will invest around Rs 10-15 crore on the basic research programme. 

India’s Vaccine Production and Demand

The lack of an effective health care system in India is accompanied with the high incidence of communicable diseases. Between 1988-93, under 5 year mortality rate in India was 122 per 1000 live births, or an estimated 3 million Indian children die under the age of five each year, while an equal number become disabled due to diseases.

According to recent reports, immunization coverage of children 12-23 months old in India was – for BCG 80%, for DPT 77%, for OPV 78%, for measles 60%, for TT 80% respectively. Number of reported cases of some diseases in 1999 in India were Pertusis – 1264, Diphtheria – 1786, Polio – 2817, Measles – 23013, Tetanus – 2125. In May 2001 only 14 cases were reported of wild polio from India.  

Department of Biotechnology (DBT) has initiated several R&D projects for the development of improved vaccines. These vaccines could replace poorly performing conventional ones, or broaden their target range of communicable diseases. The emphasis is on the build-up of a domestic capability in vaccine production. Vaccination against polio, tetanus and diphtheria, measles and hepatitis B as the Expanded Programme of Immunization (EPI) is India’s commitment to international goal of ‘Health for All by the year 2000.’ DBT emphasizes the need to control additional major communicable diseases like tuberculosis, leprosy, diarrhoeal diseases, malaria and filaria.

In 1993, the total turnover of Indian production of human vaccines at manufacturers level was around US$ 33 million. The country had been spending to the tune of US$ 12 million on imports of primary vaccines until recently. The vaccine market in India is currently approximately $100 million growing at the rate of more than 20% per year according to one estimate and, the potential market for all types of diarrheal vaccines alone is about $200 million. There are many private companies now working in the vaccine production, which was until recently dominated by Government owned centers. Vaccines make up around 1% of the total Pharma market currently but it is expected to be around 10% in the coming decade. According to another estimate, the vaccine market in India is between Rs 75 – 100 crores and is growing at a rate of about 24 per cent per annum and is indication of growing awareness towards prevention. It is growing faster than the drugs market. It is roughly estimated that investment to the tune of Rs. 300 to 400 million can come in vaccines areas during the next five years. The hepatitis B vaccine market contributes to approximately more than 50 percent of the revenues of the total vaccines market, followed by Rabies, (Haemophilus influenzae B) Hib, chicken pox and typhoid vaccines.

Recently the Government of India has taken some initiatives to promote domestic production of vaccines. According to the New Drug Policy of 1994, the genetically engineered drugs produced by recombinant DNA technology and specific cell/tissue culture targeted drug formulations will not be under price control for five years from the date of manufacturing in India. Public sector has failed to meet the expected advancements in production and technology development. Therefore the lifting of the price control aims at attracting private sector to invest in these areas. Also importance of foreign investment and foreign subsidiaries in the production of drugs using recombinant DNA is recognized since their production in many vaccines exceeds the production by public institutes. Therefore, there is a need to restrict the list of vaccines reserved for the public sector to only a few vaccines in which heavy public investment has been made and for which the capacity in the public sector is adequate to meet India’s demand.

There are more than 30 licensed vaccine manufactures in the country including about a dozen major manufactures. Among the major producers are Serum Institute, Panacea Biotech, Bharat Biotech, Shanta Biotech, Haffkine Institute, V.H.P, Biological Evans, Sun Pharma and Aventis Pasteur. Besides, multinational firms like Johnson & Johnson, SKB are engaged in import and sale of certain vaccines in India, in addition to large number of trading companies importing from various companies abroad.

DPT (diphtheria/pertusis/tetanus booster), DT (diphteria/tetanus booster), tetanus and BCG (anti-tuberculosis) vaccines are supplied mainly by domestic producers. For typhoid, domestic production is negligible and imports meet only a proportion of the demand. There is a need for new biotech-based vaccines for HIV, cancer, diarrheal diseases, influenza virus, contraception, rotavirus, TB, malaria, H. influenzae and pneumonia.

Table 1 – Requirement of Vaccines (1999-2000)

Vaccine

Million Doses

Comments

DPT 114 Self sufficient
DT 57 Self sufficient
Tetanus Toxoid 200 Self sufficient
BCG 43 Self sufficient
Polio 134 Self sufficient (Producing Oral vaccine)Injectable Polio vaccine advised by WHO
Measles 46 Self sufficient
MMR 7.5 Self sufficient
Rabies – Sheep Brain based 1.5 Mainly produced in India
Rabies – Cell culture based 5.0 Shifting to this type.
Hepatitis B – Plasma derived Some supply still of this type
Hepatitis B – Recombinant 500 Self sufficient
Typhoid (attenuated oral & Injectable) 50 Imported
H. influenzae Type B 5 Imported
Meningitis 2 Imported
AIDS Vaccine   Under development
Cancer vaccine   Not produced, Research is on
Dengue fever 3 Not produced

WHO’s certificate of assent

India is moving closer towards self-sufficiency in the area of vaccine production. India is being recognized for its national regulatory system for vaccine manufacturing and dispensing. India is one of the very few developing countries to obtain a certificate of assent from World Health Organization (WHO) for quality adherence in this area. The assent was given following an assessment by a high-level technical experts team of the world body. The team had examined the licensing system for vaccine manufacturing and marketing in the country and the quality standards of regulatory appraisal and laboratory practices. The assessment was done in conformity with the international protocols of the WHO. The WHO certificate is for all types of vaccine production in the country, including those employing the novel technologies such as the recombinant products. This is like a pre-qualification for all vaccine manufacturers in the country who want to obtain WHO-GMP approval for their manufacturing facilities and practices. It would hence open avenues for the domestic vaccine industry to commence exporting their products.

India which had been meeting its vaccine demand almost totally by imports till a few years ago, is now self-sufficient in a host of vaccines used in the compulsory national immunization programme such as BCG, DPT, TT and MMR. In the case of vaccines against polio and hepatitis B too, the country is close to achieving self-reliance. While polio vaccination is compulsory under NIP, the hepatitis B vaccine is also being regularized and may shortly be put under NIP.

Table – 2 Vaccine Manufacturers in India

No.

Institute / Company

Vaccines produced / Marketed

(Product Portfolio)

(1) Central Research Institute, Kasauli, Himachal Pradesh (Public Sector) DPT, DT, tetanus, cholera and typhoid through fermentor and other conventional techniques
(2) BCG Laboratory, Quindy, Madras (Public Sector) BCG vaccine
(3) The National Institute of Immunology (NII), New Delhi Applying biotechnology for vaccine development, anti-fertility vaccine
(4) The International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi Production of a recombinant version of the anti-fertility vaccine.
(5) Hoechst-Roussel Development and import of oral and injectable vaccine against typhoid, rabies vaccine
(6) Cadila Pharmaceuticals, Ahmedabad Development and import of oral and injectable vaccine against typhoid, Hepatitis B (Recombinant)Leprosy vaccine (Leprovac), Rabies vaccine
(7) Cadila group, Alidac Importing and marketing an anti-rabies vaccine
(8) Glaxo-Wellcome DTP (diphtheria/ pertussis/ tetanus)‘Twinrix’ (Combination Vaccine for Hepatitis A & B)
(9) Biological Evans Ltd. DTP (diphtheria/ pertussis/ tetanus) productionHepatitis B vaccine, Anti-tetanus serum
(10) Serum Institute of India DTP (diphtheria/ pertussis/ tetanus), Hepatitis B vaccine, Combination vaccine for (Tetanus-Diphtheria-Pertusis-Hepatis), Measles Vaccine, MMR vaccine
(11) Panacea Biotech, Punjab Hepatitis B (Enivac-B), Oral polio vaccine, Anthrax Vaccine (Recombinant), Ecovac-4 (Combination vaccine for DPT & Hepatitis)
(12) Shantha Biotech, Hyderabad Hepatitis B (Shanvac-B) and oral polio vaccine
(13) Wochardt Ltd., Mumbai Hepatitis B vaccine (Biovav-B)
(14) Bharat Immunological and Biological Corporation Ltd., Bulundshar, New Delhi. Polio vaccine and Importers of vaccine.
(15) Indian Immunologicals Limited, Hyderabad. FMD vaccine, Rabies DNA vaccine and Poultry vaccines.
(16) Indian Vaccines Corporation Ltd., Gurgaon Inactivated Polio vaccine, Rabies and Measles vaccine.
(17) Bengal Immunity Ltd., Calcutta (Public sector) Triple Vaccine i.e. DTP (Diphtheria-tetanus-pertusis) vaccine.
(18) Haffkine Biopharmaceuticals Corp. Ltd., Mumbai. (Public sector) Oral Polio Vaccine, Tetanus toxoid,
(19) Smithkline Beecham International Hepatitis B vaccine (Energix-B), Tritanrix-HB for (Tetanus-Diphtheria-Pertusis-Hepatitis)
(20) Torrant Scitech (I) Pvt. Ltd., Ahmedabad. 20 million doses per annum of Hepatitis B vaccine.
(21) Pasteur Institute of India at Coonoor in Tamil Nadu Rabies Vaccine
(22) Vaccine institute of Belgaum Rabies Vaccine
(23) Institute of Animal Health and Veterinary Biologicals (IAH&VB), Hebbal in Bangalore Rabies Vaccine
(24) Aventis Pharma India Limited(Markets Rabipur , Morupar and Vaxem Hib which are brands from a leading international vaccine company Chiron S.p.A based in Italy. Typhoral is the only oral typhoid vaccine that is made in Switzerland by Swiss Serum and Vaccine Institute, Berne) Rabies Vaccine (Rabipur), a conjugate Hib vaccine (Vaxem Hib), a MMR vaccine (Morupar) and an oral typhoid vaccine (Typhoral), Influenza vaccine, Pneumococcal vaccine, Hib + DPT (TETRHIBEST) .
(25) Human Biologicals Institute of Indian Immunologicals Limited Rabies Vaccine (Abhayrab)
(26) Institute of Preventive Medicine IPM, Andhra Pradesh Rabies Vaccine (NTV)
(27) Bharat Biotech India Limited (BBIL) Hepatis B vaccine (Revac-B), Malaria vaccine (in future plan), Rotavirus vaccine (under development)
(28) Intas Pharmaceuticals, Ahmedabad Hepatitis B vaccine
(29) VHB Pharmaceuticals, Mumbai Hepatitis B vaccine (Plasma derived & recombinant)
(30) Pfizer India Markets Shantha Biotech’s Hepatitis vaccine to international market under the trade name HepaShield
(31) Zydus Cadilla Rotavirus vaccine (under development), Typhoid vaccine (Injectable)
(32) Wyeth Lederle Limited Tetramune (For Tetanus-Diphtheria-Pertusis- Hepatitis), Hibtiter a ‘Haemophilus b conjugate vaccine’, ‘Pnu-Imune,’ a pneumococcal vaccine
(33) Glaxo SmithKline (GSK) DTP-HB vaccine – Tritantrix-HB, Hib vaccine conjugate with tetanus toxoid (HIBERIX), Typhoid (injectable)
(34) Human Biologicals Institute of Indian Immunologicals Limited (IIL MMR Vaccine for Measles-Mumps-Rubella)Abhay DT, Abhay TRIP and Abhay Tox (for Diphtheria-Tetanus, Triple vaccine & tetanus toxoid)
(35) Aventis Pasteur Meningococcal polysaccharide Vaccine (A + C), Oral Polio vaccine, BCG vaccine
(36) Biomed Limited Oral Polio Vaccine

Rabies Vaccine:

It has been estimated that of the 18-lakh dog bites reported each year in India and the country reports over 40,000 rabies deaths every year. The World Health Organization has shown concern over the slowing down of the ant-rabies action programme in the country. 

Rabies vaccine for human beings is of two types. One is the nerve tissue and the other is the cell culture vaccine. Most of the victims (three-fourths) of dog-bites receive nerve tissue vaccine (NTV). The former is a 100-year-old vaccine, which is injected on the abdomen for a fortnight. Currently, all private hospitals and the National Institute of Mental Health and Neuro Sciences have switched to the modern cell culture vaccine. India is among the few countries in Asia, which still develops rabies vaccine from harvested brain of sheep. World Health Organisation (WHO) has requested the Indian government to develop an alternative technique for producing rabies vaccine. WHO has classified nerve tissue vaccine (NTV) technology as ‘outdated and highly reactionary so as to cause fatal neuro-paralytic action and vaccine failure’ and called for the production of cell culture vaccine, which is more safe, efficacious and less painful. 

There are two types of vaccines for rabies: Preventive and post infected variety. Those who are injected with the preventive vaccines are the laboratory testing officials working on rabies vaccine, forest officials and others dealing with animals. The post-infected vaccine is commonly used and the cost is the only concern for most users as it is out of reach for the common man.

The total anti-rabies vaccine market was Rs 213.40 crore in July 2000 and Rs 268.99 crore in July 2001. There are 12 centers in the country, which manufactured the vaccine for rabies. There is one in Karnataka at the Vaccine institute of Belgaum, the other being Pasteur Institute of India at Coonoor in Tamil Nadu.  The Pasteur Institute of India has made a breakthrough in developing rabies vaccine through tissue culture. Vaccine developed will be at almost one-third cost of the vaccine developed by similar technologies outside India. The technology for rabies ‘Vero Cell Derived Purified Rabies Vaccine’, developed by the Pasteur Institute would has replaced the current method of developing Nervous Tissue Vaccine (NTV) that is harvested from sheep brain, as is the case with Tissue culture vaccine (TCV).

The Institute of Animal Health and Veterinary Biologicals (IAH&VB), Hebbal in Bangalore has commenced the manufacture cell culture rabies vaccine for human beings. The government of Karnataka distributes the rabies vaccine free of cost in government hospitals. The cost of the vaccine imported from France, was priced at Rs 500 and the patients were prescribed 5 vials for 5 days. Animal rabies vaccine is produced in Bangalore at the IAH&VB.

Aventis Pharma India Limited’s Rabipur, is the number one for anti rabies vaccine in India while Cadila Pharmaceuticals Ltd.’s Verorab is the next competitor. Rabipur vaccine manufactured by Hoechst was popular among doctors in the country and the other vaccine that was recommended by general practitioners was the imported variety.

The Hyderabad-based Indian Immunologicals Ltd will launch the country’s DNA vaccine for rabies very soon. The vaccine would be used only in dogs in the first phase of the launch, while plans are to make it a post-bite stage vaccine for humans.

Precisely, the vaccine for humans would be a combination of the DNA vaccine with a compatible tissue culture-based vaccine. Currently, rigorous pre-clinical testing of the combination is carried out by the company along with National Institute of Nutrition and pool of scientists with department of biotechnology (DBT) institutes. 

The Institute of Preventive Medicine (IPM) is one among the nine institutions in the country that is still producing the nerve tissue vaccine (NTV) for rabies. IPM attached to the Andhra Pradesh government is planning to set up a state-of-the-art manufacturing facility for the production of cell culture rabies vaccine. The IPM has approached the Drug Controller General of India (DCGI) for getting the marketing approval. IPM’s proposed manufacturing facility will be along with its existing unit at Nacharam near Hyderabad, and will have a capacity to produce 10 lakh doses of vaccine per annum.

Human Biologicals Institute of Indian Immunologicals Limited (IIL) manufactures Abhayrab – the antirabies vaccine marketed through exclusive outlets called Abhay Clinics spread all over the country. Direct selling has resulted in price reduction considerably and it will be Rs 200 per dose as against Rs. 300 per dose of other brands.   

The introduction of a DNA vaccine for rabies is regarded as a major step towards curbing rabies.  DNA vaccine from Indian Immunologicals would be priced substantially lower than all vaccines currently available in the market and would have a higher level of immunity profile in humans. 

Hepatitis B Vaccine

Hepatitis B affects more than two billion individuals today and about 350 million are ‘chronically’ infected with this virus worldwide. Within the framework of the expanded programme on immunisation, five member countries of the south-east Asian region-Bhutan, Indonesia, Maldives and Thailand have introduced HBV into their routine immunisation programme. According to WHO official, India has finalised its action plan to introduce Hepatitis B Vaccine (HBV) under universal immunisation programme by 2002. In the WHO ninth general programme of work, a target has been set to reduce new HBV carriers in children by 80 per cent by introducing HBV vaccination into national immunisation programme. The WHO has recommended vaccination against hepatitis B as the seventh compulsory childhood vaccine. At present, the total demand for the Hepatitis vaccine in the Indian market is estimated to be 500 million doses per annum. As per the recent decision, the Hepatitis B vaccine will be fifth in the government’s immunization programme, after measles, BCG (bacille calmette guerin), DPT (diptheria, pertusis and tetanus) and polio. Currently, the total domestic market in terms of dosage is estimated to be 20million and worth Rs2700million. The inclusion of Hepatitis B in the EPI (Extended Programme for Immunization) will result in mass vaccination.

  There are at least ten brands now present in Indian market, which include the products of Shantha Biotech (Shanvac-B) and Bharat Biotech (Revac-B). With other players being mere importers or formulations. Panacea’s (Enivac-B) was the second largest selling vaccine in the domestic market, after SmithKline’s {Energix-B). Ahmedabad-based Intas Pharmaceuticals introduced its own brand (Invac-B) a few months back; Serum Institute of Pune entered the market in 2001. VHB Pharmaceuticals (Mumbai), which had earlier imported the finished plasma-derived vaccine from Korea, has recently started selling its genetically engineered formulation. Biological Evans (Hyderabad) has also introduced its formulation lately. All this crowding has resulted in a price war. Competition has become so stiff that there are ‘baseless and maligning reports made in media by different manufacturers against one another. This spoils the credibility of the Indian vaccine industry. 

Manufacturers of Hepatitis B vaccine have called for a continuation of the duty (around 35 per cent) levied on the imported vaccine.

The multinational have made a representation through the Organization of Pharmaceutical Producers of India that the current production capacity of the Hepatitis B vaccine in India is inadequate to meet the country’s total requirements. Since hepatitis B is a growing health concern, the department has recommended the duty cut. Domestic producers however do not agree with this. Moreover, domestic manufacturers said since they had to pay an import duty of up to 70 per cent on raw materials, besides duty on chemicals and equipment, allowing imports at 15 per cent duty was unfair.

The existing capacity of domestic manufacturers is about 110 million doses, which is sufficient to meet the requirements of the EPI and the private market. Shantha Biotech alone has an existing capacity of 50 million doses. In 1999-2000, Shantha Biotech had a 40 per cent market share, while Smith Kline Beecham had 30 per cent of the Hepatitis-B vaccine market. Indigenous Shantha Biotech’s vaccine costs Rs 150 per dose, while the multinational firms is close to Rs 500.

Even with the imposition of 35 per cent duty, the market for the imported products has grown in terms of volume and they have also started reducing the price even after imposition of this duty. Shantha Biotech, Bharat Biotech, Serum Institute of India are manufacturing Hepatitis vaccine in India. Pfizer has a co-marketing pact with Shantha Biotech for its hepatitis-B vaccine, Shanvac-B, under the multinational’s own brand name ‘HepaShield’ in the international markets.

The company Bharat Biotech International Limited (BBIL), which claims to have the biggest manufacturing capacity for hepatitis B vaccines in this part of the world, has made their hepatitis B vaccine also more competitive. The present price of a single dose of hepatitis B vaccine manufactured by BBIL is around Rs 50. The company has sold about 200 crore doses so far. Wockhardt has planned a large capacity expansion with a new facility of international standards for its Hepatitis B vaccine “Biovac-B” which has been developed by the company through its in-house biotechnology research. The vaccine became the most successful pharmaceutical brand introduced in India during the year 2000. Shanta Biotechnics Private Ltd. (Hyderabad) is planning to set up a Rs 60 crore multi-product biotech production facility, which includes a production unit for hepatitis B vaccine and a research and development laboratory at Medchal locality in the outskirts of Hyderabad. Wockhardt will sell the recombinant DNA Hepatitis B vaccine at a price of Rs 100 per dose for the adult and Rs 50 per dose for children as against the prevalent price range of Rs 250-500 for adult dose and Rs 200-400 for children. 

Cadila Pharmaceuticals Limited (CPL) started commercial production and marketing of Hepatitis-B vaccine by November 2000. The company, has developed the technology for Hepatitis-B vaccine with its in-house R&D. Strain used for HB vaccine production matches with international standard. The vaccine is marketed under the brand name ‘VaB’. The production of first batch was 1 million doses, which will gradually go to full capacity of the plant at Dholka in Gujarat. The plant meets the requirements of WHO, GMP and other international standards. 

Since the Government of India imposed 45 per cent duty on imports of Hepatitis B in 1999, the local manufacturers have the price competitiveness for the product in the domestic market, though the imported vaccine is superior in quality. Till now, no companies have attempted to produce the import quality product in India because of lack of suitable technology and a possible cost escalation. Hence, the multinational vaccine manufacturer SKB was the leading player in the domestic HB market. 

Serum Institute of India (SIIL), which has acquired the Hyderabad-based hepatitis-B vaccine company –Transgene Vaccines in 1999, will shift the entire plant and technology to Pune shortly. The company is planning to launch its brand of hepatitis- B vaccine by April 2001. It began small level of production in Hyderabad plant of Transgene but mass scale production will take place later. The company is proposing to produce 1,200 million dozens of vaccine. The technology of Transgene Vaccines for Hepatitis B vaccine is one of the best in the world. Rein Biotech, Germany, originally developed it. Wochardt also uses the same technology. Serum Institute of India is currently a major producer and exporter of DTP, Measles and Rubella vaccines in the country. SIIL is also planning to introduce a quadruple vaccine combining hepatitis-B vaccine along with DTP vaccine.

Haffkine BioPharmaceuticals Corporation Ltd, a Maharashtra government enterprise will also start commercial production of Hepatitis B vaccine. In-house research team of Haffkine Biopharma has developed the vaccine.

Panacea Biotec at its Lalru plant in Punjab will produce 70 million doses of Hepatitis B vaccine with the technical support of the Havana-based Center for Genetic Engineering & Biotechnology. 

Dengue vaccine

Dengue is the most widespread mosquito-borne viral disease. In 1997, it was present on most continents and will continue to spread as newly urbanized areas become infested with mosquito vectors. In those areas where Dengue is endemic, 1.5 billion people including about 600 million children are at risk. Each year, it is estimated that from 50-100 million people are infected and that tens of thousands of children die from this viral infection. Dengue Fever afflicts between 50 and 100 million people yearly in tropical and subtropical regions. The disease occasionally afflicts North India. Two years back, around 250 people died of dengue in Delhi. Global rise in temperature could increase the range of Dengue and malaria-bearing mosquitoes and result in an additional 50 to 80 million cases each year.

The US- based Hawaii Biotechnology Group, Inc. (HBG) will file patents for Dengue vaccine in six months. India will be a major market once the vaccine is marketed, as North India is a dengue-prone area. At the rate of $1.5 per vaccine, India might be a $ 4 million market for their vaccine. Following the pharmaceutical industry’s ten-year average for the development of any new vaccine, it estimates a worldwide market that could reach $100’s of millions by the year 2008. Live vaccine is cheaper but imparts variable immunization. Aventis Pasteur, another vaccine manufacturer is developing genetically engineered chimeric dengue/yellow fever virus product. HBG’s approach involves incorporation of gene of Dengue fever parasite in E.coli, which is then grown in large quantities. The protein of interest is then purified and is used as the core of the recombinant DNA vaccine. This vaccine is cheap as well as safe since it does not use attenuated live parasite for vaccine production.

Anthrax Vaccine

Panacea Biotech has bought rights for production and marketing of the non-toxic anthrax vaccine developed by JawaharlalNehruUniversity. The vaccine will be commercialized over the next six to eight months once the necessary trials and registration are completed. Since the vaccine falls under the category of life saving or emergency drugs, the registration will be undertaken under the fast track registration scheme of the government of India and will be completed much faster.

The company has entered into a ten-year agreement with Biotechnology Consortium of India Limited (BCIL), a government of India undertaking engaged in commercializing technologies developed by government laboratories. The vaccine now developed is a recombinant one and does not contain endothelial factors and lethal factors thus providing the vaccine much higher safety and efficiency levels. This recombinant vaccine has already gone through basic toxic trials and will undergo the human clinical trials soon. Panacea has a US-FDA-approved plant for the production of this vaccine.

Polio Vaccine

Under the Pulse Polio Immunization (PPI), widely publicized over the print and electronic media, 13.59 crore Indian children in the age-group of 0-5 years were given doses of oral polio vaccine in the country on 6 December 1998 and 13.84 crore children in the same age-group were given oral polio vaccine on 17 January 1999. Despite such gigantic efforts so far, 5-7 per cent children are still not immunized under PPI. A system of surveillance for cases of acute flaccid paralysis has been set up for the detection and containment of poliomyelitis all over the country.

India uses oral polio vaccine for immunization programme. Although there are some doubts of safety of oral live vaccine we have not shifted to killed (inactivated) injectable vaccine. European countries such as the Netherlands, Finland, and Denmark have been using the intramuscular polio vaccine (which contains the killed virus) right from the beginning while USA also uses now the inactivated vaccine. But experts feel that our risk benefit ratio still does not prompt us to use killed vaccine instead of live one.

As long as immunization with live oral vaccine continues, the risk of associated paralytic poliomyelitis will exist. WHO has suggested three doses of oral polio vaccine (OPV) and one dose of injectable (killed) polio vaccine (IPV). The Department of Biotechnology may shortly commence the production of injectable polio vaccine (IPV) in India.

Department of Biotechnology along with National Institute of Immunology, the South Campus of Delhi Universtiy and Center for Biochemical Technology is developing the vaccine.

Haffkine Biopharmaceuticals produces and supplies polio vaccine to government owned institutions. Panacea launched its introductory product oral polio vaccine in 1995 and continues to be the largest supplier of the vaccine to the pulse polio programme supported by UNICEF.

Leprosy vaccine

The World Health Organisation (WHO) had set a goal in 1992 to eradicate leprosy from the world by 2005. About 600,000 to 650,000 new leprosy cases were added on to the world population every year. About 60 per cent of leprosy cases were in India and Brazil while another 39 per cent were in 15 other countries. The remaining were scattered throughout the world including the US.

The Union health ministry has not accepted the proposal from the department of biotechnology (DBT) to include an indigenously developed leprosy vaccine in the national immunization programme. The ministry’s decision was based on the report of an expert committee, which found that the vaccine does not fit the requirement of the ongoing leprosy elimination project.

Ahmedabad-based Cadila Pharmaceuticals markets leprosy vaccine under the brand name ‘Leprovac’. This vaccine is the result of years of research by the New Delhi-based National Institute of Immunology, an affiliate body of the department of biotechnology. The clinical studies of the vaccine were held for over ten years with active participation of the health ministry. The trials had proved the prophylactic as well as therapeutic uses of the vaccine. Cadila Pharmaceuticals has just commenced production of vaccine for leprosy developed by the Talwar Research Foundation, New Delhi. The new vaccine is the answer to eradicate leprosy in India. It helps to cure the disease and upgrade the patient’s immunity quickly.

The vaccine is developed for ‘multi-bacillary’ patients who are those with extreme immune deficit.

Malaria Vaccine

The New Delhi division of the International Center for Genetic Engineering & Biotechnology (ICGEB) along with the US-based non-profit organization, PATH (Program For Appropriate Technology In Health) and the Hyderabad based Bharat Biotech International will work for further development of its vaccine candidate for Plasmodium vivax (P.vivax) malaria, which is rampant in India and many other developing countries. As per an agreement signed, the Malaria Vaccine Initiative (MVI) of PATH will fund the clinical trials and technological upgradation of the vaccine, which is now at the laboratory-stage with ICGEB.

MVI has already brought $1million to the project following the agreement. Bharat Biotech is likely to take up manufacturing of the vaccine at a later stage. It will also conduct the clinical trials of the product in compliance with specified biological standards. 

Nearly 65 per cent of malaria cases reported in India are caused by P.vivax parasite and almost half of the total health budget of Indian government is now spent to combat malaria. While P.vivax malaria is more prevalent in India and across other Asian countries, Latin America and Africa, the other variant P.falciparum, which causes death, is found mostly in Africa. Currently no vaccine is licensed to protect against any form of malaria though it infects 300 to 500 million people worldwide.

Rotavirus vaccine

Rotavirus, which causes diarrhea in children, is the primary reason for infant mortality in the world. International research focus has long been on finding a rotavirus vaccine with variants of the virus being detected even in developed countries like the US. Nearly 1.5 lakh children are succumbing every year to the rotaviral diarrhoea alone in India. 

Global market for the rotavirus vaccine is more than 1 billion dollars. Permission for phase I clinical trials on a candidate vaccine against rotavirus developed jointly by the Indian Institute of Science, Bangalore and the All India Institute of Medical Sciences has been granted by Drug Controller General of India (DCGI). The condition is that the trials should be multi-centric. The strain would be put in Phase II trials in the US soon. DBT will collaborate with domestic companies Zydus Cadila and Bharat Biotech for Phase II and III trials in India. The candidate vaccine developed by the two domestic institutes is a product of the India-US Vaccine Action Programme. DBT has supported these institutes in the project.

The Hyderabad based Bharat Biotech International Limited, the country’s leading Hepatitis-B vaccine manufacturer, is likely to bag the exclusive manufacturing and marketing rights for rotavirus vaccine, developed after a decade long Indo-US joint research carried out under the Indo-US Vaccine Aid Programme (VAP). The company is planning to invest Rs 10 crore for setting up of the manufacturing facilities. The commercial production of the vaccine, which will be developed with Indian rotavirus strains, is expected to commence within three years. 

Meningitis Vaccine

Wyeth Lederle is known for its Hibtiter a ‘Haemophilus b conjugate vaccine’ for hib meningitis, a disease, which affects 33 per 1,000 children under five years. The vaccine is priced at Rs. 500 a vial for one dose and Rs. 3,000 for a multi-dose [10 doses]. The World Health Organisation approves it. The vaccine is still unaffordable to a majority of the population in India. It is only available in leading hospitals in the country.

Pneumococal Vaccine

Wyeth Lederle company also produces is ‘Pnu-Imune,’ a pneumococcal vaccine. It is polyvalent, to prevent pneumonia, meningitis and bacteremia in high-risk patients above 60 years. Launched about eight months ago in Karnataka, Wyeth Lederle has marketed 100 vials of Pnu-Imune per month and the cost per vial, which includes a disposable syringe, is Rs. 700. The vaccines are being imported in finished form from its US based parent. The vaccine is a success worldwide and meant not only for children above the age of two but can also be administered to adults over the age of 50.

AIDS Vaccine

The first HIV vaccine effective on the genetic variant of the organism found in Asia and Africa (HIV-1 subtype C) would be delivered by India very soon. The vaccine is developed by All India Institute of Medical Sciences (AIIMS), New Delhi. Department of Biotechnology (DBT) has already yielded one candidate vaccine for subtype C with good immunity profile for subtype B, which is prevalent in Europe and the United States as many as 35 candidate vaccines have been developed in various parts of the world. While, the genotype HIV –1 subtype C is largely prevalent in all South Asian countries including India, southeast Asian region and South Africa.

Four centrally coordinated projects aimed at development of India-specific HIV vaccine are currently on. While AIIMS has already come out with a candidate vaccine, which would be entering clinical trial stage in a few months, other three centers have also reported encouraging results. Pune-based National AIDS Research Institute and National Institute of Virology are into a joint research project. Bangalore-based JawaharlalNehruCenter for Advanced Studies and the NationalCenter for Cell Sciences, Pune are the two other firms engaged in HIV vaccine research.

Chiron Corporation, Merck and GlaxoSmithKline are working on AIDS vaccine. Chiron’s AIDS vaccine will be different as it will inject the DNA and give a booster dose of the recombinant form into patients for better results. Chiron’s AIDS vaccine will begin clinical trials soon and commercial production may begin after 6 years. Chiron will develop novel DNA and alphavirus replicon-vectored vaccine candidates based on HIV-1 subtype B (or “clade B”) strains prevalent in the US and Europe. As part of the contract, the company will simultaneously work on a vaccine to protect against subtype C viruses, the most common HIV strains in sub-Saharan Africa, China, and India.

The Indian Ministry of Health and Family Welfare is also going in collaboration to develop AIDS vaccines suitable for India. Indian Council for Medical Research (ICMR) provides a framework for joint projects in vaccine design, buildup of capacity for clinical trials and transfer of appropriate vaccine manufacturing technology to India. There is one programme of partnership between Therion Biologics, a biotech company in Cambridge, Massachusetts with visiting Indian scientist Sekhar Chakrabarti of National Institute of Cholera and Enteric Diseases in Calcutta. Chakrabarti is now cloning and sequencing genes from one of the isolates and will bring the subcloned sequences to Therion for vaccine construction. Therion will transfer the technology to an Indian vaccine manufacturer, which will produce lots for eventual Phase II/III clinical trials. National AIDS Research Institute (NARI) in Pune is characterizing HIV isolates from several recent seroconverters in the region, where NARI will conduct clinical trials of the candidate vaccine.

Cancer Vaccines

Dabur Oncology plc, a 100 % subsidiary of Dabur India Ltd in the UK, will shortly enter into a major collaboration with a leading British institute for fundamental research in cancer vaccines and diagnostics.

Measles Vaccine

Serum Institute of India is the largest supplier of measles vaccine in the world and also for the WHO aided vaccination programmes. Serum Institute of India (SIIL), has tied up with the San Diego-based Universal Preservation Technologies Inc (UPT) and the Bill and Melinda Gates Children’s Vaccine Program at PATH, to assess the feasibility of developing a thermo-stable measles vaccine using UPT’s VitriLife vaccine preservation technology with SIIL’s live attenuated measles vaccine for use in the developing world.

The UPT VitriLife process is a patented method for the industrial scale preservation of biological suspensions such as proteins, enzymes, viruses, bacteria and cells, at or above room temperature. The process is gentle and allows preservation of both animal and human viral and bacterial vaccines at higher yields and with improved temperature stability compared with conventional preparation procedures. If this application is feasible then there will not be a need of cold chain for the vaccine during its transport and further storage. It will save lot of expenses of cold storage in the developing countries.

MMR Vaccine

Vaccination against Measles, Mumps and Rubella is not a part of routine immunization in India. MMR is not produced in India but is imported. Human Biologicals Institute of Indian Immunologicals Limited (IIL) will be manufacturing MMR (Measles, Mumps, Rubella) vaccine soon.

Diphtheria-Tetanus-Pertusis vaccine

Many manufacturers like Haffkine Institute, Biological Evans, Serum Institute of India etc. produce diphtheria-Tetanus-Pertusis vaccines in India conventionally. This is one vaccine for which India is self-sufficient since quiet some years. Human Biologicals Institute of Indian Immunologicals Limited (IIL) will have branded vaccines like Abhay DT, Abhay TRIP and Abhay Tox by the end of 2001. While Abhay-Trip is a combination of purified diphtheria toxoid, purified tetanus toxoid and B Pertussis vaccine, Abhay-DT (Diphtheria and Tetanus toxoid adsorbed) is a vaccine containing a combination of purified diphtheria toxoid and purified tetanus toxoid and Abhay Tox, a tetanus toxoid. Tetramune Vaccine – Wyeth Lederle Limited, one of the leading players in the vaccine business in India may soon start manufacturing of Tetramune, an advanced vaccine for diptheria, tetanus toxoids and pertusis. The company has successfully launched this single vaccine in Karantaka recently. The vaccine is ideal for children who are not yet exposed to DPT (diphtheria, polio and tetanus) vaccine. Tetramune, which is priced at Rs 520 per vial, is currently imported from the United States and has undergone drug safety trials at the government of India drug testing laboratory at Kasauli in Himachal Pradesh before it was launched. Vaccine for pertusis of acellular type is not available in India.

Cholera Vaccine

The recombinant cholera vaccine developed under the supervision of the department of biotechnology. (DBT) has obtained the US patent for the strain. Shantha Biotechnics is likely to buy the technology of VA-1.3, the recombinant DNA vaccine strain developed jointly by Sanjay Gandhi Post-Graduate Institute, Lucknow and the National Institute on Cholera & Enteric Diseases, Calcutta. Phase I trials have been completed and Shantha Biotech may join in the phase II stages shortly. While the organism keeps on making genetic shifts, the scientists with the Institute of Microbial Technology, Chandigarh and Institute of Chemical Biology, Calcutta had managed to remove the toxic genes and even then retain the immunization potency.

Typhoid Vaccine

In the meeting of National Vaccine Board (NVB), Government of India, in 1995-96 it was decided by consensus to discontinue the manufacture of the cholera and typhoid vaccines by the old conventional methods since these vaccines were not very effective. Subsequently, the manufacturers of these vaccines in all the states were advised to discontinue production by the old conventional methods. The typhoid vaccine was, however, not part of the National Immunization Programme (NIP). The oral and injectable typhoid vaccines currently available in the market cost approximately Rs 165 and Rs 238 respectively, keeping it outside the reach of several consumers. Haffkine Bio-Pharmaceutical Corporation Ltd HBPCL’s (HBPCL) typhoid vaccine was at Rs 9.40 per vial of 5 ml (plus local taxes) in 1996, annual supply has been in the region of around five lakh doses. The IndianAcademy of Paediatrics (IAP) had expressed concern over the non-availability of the cheaper typhoid vaccine. The typhoid vaccines currently available in the market use sophisticated and costly technologies. These imported vaccines are supposed to give higher and lasting immunity, but cannot be given to children below two years, as they are not effective in that age group. HBPCL’s typhoid vaccine, prepared by the conventional methods, has been ‘good’ and ‘effective’ within its limitations of the duration and the level of immunity. HBPCL will reinitiate the typhoid vaccine production.

Combination Vaccine

DPT-HB combination

India is lagging behind in the production of combination vaccines. While there are about 17 combination vacines in most of the foreign countries, our knowledge is limited to a few like the polio vaccine, DTP, DT and MMR.

Less number of injections is the obvious advantage of combination vaccine. Only thing the components should be complementary, compatible and not definitely inhibitory in any way to immunization effects of individual components.

Indian Academy of Paediatrics has strongly recommended the use of a combination of hepatitis B (HB) vaccine with DTP vaccine as it has been established to enhance the efficacy of HB mono vaccine. The experts from the IAP state that the results evolved in the immunization practice, the recombinant vaccine showed an increased immunity among the children against hepatitis B. Recently, the international organization like WHO, Pan American Health Organization (PAHO), Global Alliance for Vaccines and Immunization (GAVI) and UNICEF have also endorsed this recombinant vaccine for the same reason. Combination vaccine, which reduces total dosages of six to four for children, is likely to be identified for the National Immunisation Programme by the government of India. 

There is only one brand of this combined vaccine currently available in India which was introduced by Glaxo SmithKline (GSK) in October last year, there is another brand from the Pune-based Serum Institute of India which is expected to hit the market by the end of 2001. GSK’s DTP-HB vaccine – Tritantrix-HB, according to experts from IAP, has not been subjected to thorough clinical trials in the country before approving for marketing. Hence, it is not yet proved fully effective and suitable for Indian environment, though it has been in use since the approval. SIL’s recombinant vaccine   has shown the enhanced effect of hepatitis B immunity in trials. Tritantrix-HB of GSK was priced at Rs 1000 per vial of ten doses while Serum Institute of India has not decided the price.

SmithKline Beecham International has launched combination vaccine Tritanrix-HB. This is first of its kind in the world and also in India. The new vaccine combines four antigens – Diptheria, Tetanus, whole cell pertussis and Hepatitis B. Tritanrix-HB is a vaccine that combines the DTP (Diphtheria, Tetanus, Whole cell pertussis) vaccine with Engerix-B – the vaccine against Hepatitis B. With combination vaccine 80% population will also get immunized against Hepatitis B. The vaccine is introduced in 1996 and is available in 80 countries. It has been approved by, both the World Health Organisation (WHO) and the Pan American Health Organisation (PAHO). The vaccine is priced at Rs 1,099 for a multi-vial (5 ml) for 10 paediatric doses, plus the taxes and is at par with those of individual vaccines’ total. The vaccination schedule is exactly the same as that for DTP vaccine i.e., six weeks, ten weeks and 14 weeks.

Glaxo India has received the approval of the Drugs Controller General of India (DCGI) to manufacture and market a combination vaccine for hepatitis A and B and will come to market very soon. The new vaccine, a recombinant product, will be branded ‘Twinrix’. Currently there is only one ‘Hepatitis A’ vaccine ‘Havrix’ available in India and that is from SmithKline Beecham. Hepatits A vaccine has 8 times the cost of that of Hepatitis B vaccine.

Panacea Biotech has announced the launch of Ecovac-4, the combination paediatric vaccine of DPT with hepatitis B vaccine. The components used for combination vaccine are brought from abroad (thus tested), hence there was no need of multicentric testing for their vaccine. There are three other companies, Serum Institute of India at Pune and Shanta Biotechnics and Bharat Biotech based in Hyderabad, which are still conducting clinical trials of the same DPT-HB combined vaccine at various centers in the country.

Aventis markets a combination vaccine for Haempophilus influenzae (Hib) and DPT, which is trademarked as TETRAHIBEST.

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