Swine Flu in India – Are we prepared?

This is festival time in India. The festivities for Ganesh chaturthi and Eid barely over, this weekend is the culmination of Vijaydashami, celebrated across India in various forms. Whether it is Dussehra, Dasara, Dashahara, Navaratri or Durgotdsav, the common theme is victory of good over evil. Large crowds gather every day in temples and puja pandals across India.

In times of a flu outbreak, this is a public health nightmare. This year’s Ravana is the microscopic influenza A H1N1 (2009) virus. Will the arrows of public health preparedness be able to slay this new age Ravana? This unlikely in India, if you listen to what experts have to say.

I wrote earlier about the 3.1% mortality among swine flu cases in India. The latest Ministry of Health and Family Welfare (MoHFW) release is for September 24, 2009; it reports 8979 cases and 277 deaths – 3.08% mortality.

Prof. T. Jacob John, unarguably India’s most prominent public health scientist, thinks this high mortality could be due to a selection bias – those with more severe illness are being tested. So, what has been India’s testing policy? A larger question is how has India dealt with this outbreak from a public health perspective.

An editorial in the August issue of the Indian Journal of Medical Research (IJMR) written by Prof. Jacob John and Prof. Jayaprakash Muliyil, provides a very frank and analytical assessment. It also provides sagacious advice to the Government on what it should and should not be doing.

The editorial can be read at http://www.icmr.nic.in/ijmr/2009/august/editorial1.pdf (I am grateful to the authors and the Editor, IJMR for their permission to post this link).

They say, and I quote – “At the request of the World Health Organization (WHO), many countries including India had made a detailed Pandemic Preparedness and Response Plan (PPRP). Many experts believed that India would, for the first time in our history, be well prepared to face an epidemic.-------- The events that took place in June, July and up to mid-August (as we write this) are still fresh in our memory. The expectation that India would face the pandemic with confidence and competence gradually gave way to disappointment and dismay. While the virus is reaching many places and spreading among the population, as anticipated, India does not have a public health infrastructure that could put into practice the PPRP”.

Prof. Jacob John agreed with my call in an earlier post and adds – “Science must guide policy. Policy must drive public health. So public health interventions must be evidence-based”.

Those who matter at the MoHFW and Indian Council of Medical Research will do well to read this editorial (which is in their own journal), and to ensure that policy is driven by science and not the other way around.

A Vaccine for AIDS

The human immunodeficiency virus (HIV), which causes AIDS, has been a difficult target for vaccine developers.

Vaccines are substances that mimic a pathogen to raise immunity in the host (human), which disables (neutralizes) and clears the pathogen from the body in the event of a natural infection.

Two types of immune responses are required for complete protection. These include humoral responses in which antibodies develop to neutralize extracellular pathogens, and cellular responses in which special cytotoxic cells are recruited to kill host cells that have become infected. An ideal mix of the two types of responses are required, and this mix is different for different pathogens.

The problem in the HIV field has been a poor understanding of the correlates of protection. In other words, we don't understand the quality and quantity of humoral and cellular responses that are required to prevent HIV infection. The problem is compounded by the extremely variable nature of HIV, which enables it to evade host immunity.

September 2009 has been a good month for HIV/AIDS vaccine efforts.

On Sept 3, a paper published in the journal Science, by a consortium of scientists led by the International AIDS Vaccine Initiative reported the discovery of two neutralizing antibodies, which target a potential Achilles heel on the virus surface. The discovery was the result of a global effort to search for antibodies in people who naturally control HIV infection. This is likely to provide important clues for engineering better vaccines. 

Good news was released today from a vaccine trial conducted jointly by the US Military HIV Research Program and the Thai Ministry of Public Health. This trial initiated in 2003 was a Phase III efficacy study of a prime-boost combination of two vaccine candidates - ALVAC, a bird pox virus carrying the HIV envelop protein (gp120) gene manufactured by Sanofi-Pasteur, and AIDSVAX, a recombinant form of gp120, manufactured by VaxGen (now Global Solutions for Infectious Diseases). Both of these candidate vaccines were earlier tested individually and found to have no efficacy.

The results released today showed a 31% efficacy for a prime-boost approach using these two vaccine candidates. Though the efficacy is not impressive, this is the first time a candidate AIDS vaccine has shown any level of protection in humans.

More details on the antibody discovery and the vaccine trial are available from the following sources:
International AIDS Vaccine Initiative: http//www.iavi.org
US Military HIV Research Program: http://www.hivresearch.org/
Science magazine:  http://www.sciencemag.org/cgi/rapidpdf/1178746

Swine Flu in India

The last situation update from WHO puts the number of positive cases worldwide at over 296,471 with at least 3486 deaths (http://www.who.int/csr/don/2009_09_18/en/index.html).

India's Ministry of Health and Family Welfare (MoHFW) puts out daily updates on the swine flu situation in the country (http://mohfw.nic.in/press_releases_on_swine_flu.htm). The updates started on August 1, 2009, by which time there were already 534 positive cases but no deaths. The first death, a 14-year old schoolgirl from Pune, was reported on August 3, 2009. Since that time, the number of positive cases have gone up steadily. As I write this, the last MoHFW update from September 21, 2009 reports that samples from 35,148 persons have been tested across the country, 8153 (23 .1%) have been found positive and 257 persons have died as a result of this infection.

The mortality rate in India stands at 3.1%, compared to a global average of 1.1%. What is the reason for this higher mortality in India? We don't know as there is no epidemiological analysis available. The reasons could be
(a) virological - increased virulence of the virus circulating here,
(b) host genetics - maybe Indians are genetically predisposed to get more severe disease
(c) environment -  poor healthcare infrastructure, late reporting of cases, selection bias with only severe cases being tested, etc.
It could also be an interesting mixture of all of the above.

The point is - unless we look at these issues systematically, we will not know.

I have made a graph on the situation in India based on MoHFW updates. The plot shows positive cases and deaths every 5 days from the start of updates (Aug 1, 2009) for the first 50 days of reporting.

 

It is quite clear from the graph that the outbreak in India is growing at a steady rate. Since early in the outbreak, the number of cases have gone up  at the same rate. The pink line in the graph has a constant slope. Curiously, the death curve shows a hint of biphasic nature to it. The death rate seems to be picking up lately. After running almost parallel with the positive cases curve for some time, the death curve has now intersected it.  Will it continue its upward spiral? In the absence of any analysis or models, only time will tell.

India has done well in gearing up resources to put testing in place. Scientists and technicians involved in testing for swine flu have done an admirable job. They have used all the resources at their command to test quickly and have adhered to quality.

But this is only half the job done. We should be analyzing this outbreak. The Indian Council of Medical Research (ICMR; http://www.icmr.nic.in/), whose mandate is medical research, should be driving this. We have a National Institute of Epidemiology, an ICMR institute in Chennai (http://www.icmr.nic.in/pinstitute/nie.htm). What are those guys doing? What are the public health experts at the  Public Health Foundation of India (http://www.phfi.org/) doing? The PHFI website has H1N1 flu advice (http://www.phfi.org/h1n1flu/index.html), but no analysis.

It is the same case with virological analysis. No genomic data is available on the virus circulating in India. The Influenza Virus Resource uploads genomic data in the public domain on a daily basis. See http://www.ncbi.nlm.nih.gov/genomes/FLU/SwineFlu.html. There is no data in the public domain from India. And it is truly shameful.

Is the virus in India showing genomic signatures of increased virulence? How many mutations will it take to make it highly virulent? Are we beginning to see the H274Y mutation in the NA protein, which is reported to be associated with Oseltamivir (Tamiflu) resistance? WE DON'T KNOW.

Should we not have science drive policy? Where is the science? It is time for ICMR, PHFI, Ministry of Health, Ministry of Science and the scientific and biomedical research community at large to ask these questions.

In India, our flu season is just beginning. Wake up.

Swine Flu - a triumph for science

Influenza pandemics happen about three times in a century. At least this is what 20th century history teaches us. There was the big Spanish Flu of 1918 (which did'nt really start from Spain), which infected an estimated third of the human population at that time and killed 40 to 50 million people. Then, there were the Asian Flu of 1957 and the Hong Kong Flu of 1968, each killing an estimated 1 million persons each.

Historically we were due for another big one. Is this the one? The swine flu (again a misnomer) started in Mexico around March of this year and has gone around the world, prompting WHO to raise its alert to Level 6, the first time in over 30 years. As of September 6, 2009, this disease has infected over 277,000 persons and killed at least 3200 (see http://www.who.int/csr/don/2009_09_11/en/index.html). If you believe that in infectious diseases you only see the tip of the iceberg, there are many more infections and deaths that have gone unrecorded. And we are just getting into the flu season in the Northern hemisphere.

So far this virus appears to be mild. It has killed about 1% of infected people, many of whom had underlying problems such as asthma, diabetes, hypertension and obesity. Yes, obesity! Thats a new one positively identified for this virus. But will it remain mild? No one knows. History tells us otherwise.

The 'Spanish flu' started as a mild infection in the summer of 1918, spread rapidly and the virus got a lot of chance to mutate. By November of 1918, the flu season in the Northern hemisphere, it became highly virulent and killed with disdain. We are into a similar situation with this one. It has already gone around the world, including Australia and South America (Southern hemisphere) in their flu season, and is getting a lot of chance to transmit and mutate. Health agencies are already preparing for the 'second wave'. See
http://www.who.int/csr/disease/swineflu/notes/h1n1_second_wave_20090828/en/index.html

Are we then sitting ducks? Or pigs to be more appropriate for this one! Not really. Health systems are much better prepared to handle these emergencies today than they were 90 years ago. The agent for Spanish flu took over 11 years to identify. The 'swine flu' virus was identified in days.

This virus, technically called Influenza A H1N1 (2009), is a triple reassortant. Scientists have traced its 8 different gene segments to influenza viruses that have circulated in humans, birds and pigs (see: Garten et al, Science vol 325, pages 197-201; July 10, 2009). The cartoon below illustrates the lineage of different gene segments in this new virus.
The surface proteins of the virus - the hemeagglutinin (H1) and the neuraminidase (N1), are both of swine origin. This makes the virus new to the human population, not recognized by our immune system. This is obvious from the efficient manner in which it is transmitting between humans.

Every adversity has a lesson. The lesson here is how investments in biomedical science are paying up in unexpected ways. It took just days to identify this virus and weeks to come up with its origins. This is truly the power of molecular biology, built up over years with the Human Genome Project as a very visible high point. Many have criticized that megaproject, but consider that it enabled the development of technology, which is making all this possible. When SARS came around in 2003, the sequencing of its genome was also undertaken in facilities set up for the HGP. Chinese scientists sequenced the SARS virus genome in a facility built to sequence the rice genome! That is a great off-target effect and a lesson for science funders and planners.

Every day dozens of swine flu sequences are being uploaded in public databases (http://www.ncbi.nlm.nih.gov/genomes/FLU/SwineFlu.html). Many scientific journals, normally driven by commercial interests, have made swine flu papers "open access". This uninhibited access to knowledge and the power of internet is bringing the technical prowess of big science closer to where it matters - the hot zone.

Are we really making use of this knowledge in my hot zone - India? Stay tuned.