Commercial interests too play a very strong role since there is much money to be made for the industry, though the foundational science is public-funded.
Sputnik-1 began the Space Race in 1957, taking the world by surprise at the amazing feat of Soviet science. This was followed soon by Yuri Gagarin, as the first man to travel in Space and Valentina Tereshkova as the first woman in Space. Jolted by the successes scored by their Cold War rival, the United States poured resources into the race and scored its own spectacular first by landing Neil Armstrong and Buzz Aldrin on the moon in 1969. The decline and breakup of the Soviet Union later made the world oblivious to the enduring strengths of the Russian scientific establishment.
That was till a few days ago, when Russian health minister Mikhail Murashko announced that Russia had produced a vaccine that was given regulatory approval after less than two months of human trials. The vaccine was produced by the Gamaleya Institute, linked to the Russian defence ministry and financed by the Russian Direct Investment Fund. The vaccine was being administered to volunteers in Russia, the United Arab Emirates, Saudi Arabia, Brazil and Mexico. The prospect of obtaining and administering that vaccine has been reportedly welcomed in the Philippines and several other countries that are eager to try it out. This announcement staggered the global scientific community.
However, it has also been met by scepticism and downright denunciation by several scientists in the Western world. Some scientists in Russia, too, have expressed concerns, and the World Health Organisation has urged caution. The doubts about Russia’s claim arose because the WHO said they had only been notified of a Phase 1 trial, while the completion of a Phase 3 trial was considered essential for evaluating evidence of efficacy and safety. Classically, the Phase 1 trial is performed on a few human volunteers to see the initial response. Phase 2 sees more volunteers and more tests, with the determination of the dosage required to elicit a good immunological response. Phase 3 involves a large randomised controlled trial with several thousand healthy volunteers given the vaccine and other matched individuals given a placebo. The vaccine is ready for release only when it successfully clears Phase 3. As use in the general public increases, post-marketing surveillance is also conducted (Phase 4), to assess the failure rates and adverse effects which may not have been detected or were difficult to estimate in the Phase3 trial.
Why are such elaborate procedures needed to study potential vaccines before their release? Three critical elements which need to be determined, for a new vaccine to be judged as fit for general use, are efficacy, safety and duration of protection. Efficacy in protecting against the pathogenic microbe and a fairly long duration of protection are expectations that the vaccine must fulfil. Safety is a prime consideration, especially because the vaccine is being administered to healthy persons. ‘Do no harm’ is the first principle.
Why will a vaccine be ineffective? First, the antigen may be inappropriate or too weak as a stimulus to produce a strong immune response. Second, antibodies may be produced, but they may not be neutralising antibodies which get rid of the virus. Third, a phenomenon called the ‘Original Antigenic Sin’ may come into play. In this, the antigen which is employed in the vaccine may stimulate a strong immune response to itself. However, being a modified antigen or only a part of the virus, it may not create the imagery of the actual virus for the immune system to store and react to. The body will only recognise the vaccine antigen as the stimulus to react to, but not the virus itself! Like failing to recognise the real criminal because of a badly-done police sketch.
The vaccine can produce adverse effects, from minor to severe. So, safety becomes a very important aspect to assess. Side-effects like short-lasting fever or muscle pains may be acceptable when potential benefits are large. However, a more dangerous effect may be of ‘Antibody Dependent Enhancement’. The antibodies created by the virus provoke a serious illness by unleashing a self-destructive cascade of immunological reactions that amplify the damage caused by the virus.
Duration of protection matters because the whole effort of immunising billions of people will be worthless if the induced immunity lasts only three months.
That concern arises because of recent reports that the humoral immune response of antibodies produced in response to Covid-19 markedly declines by three months. However, cell-mediated immunity also seems to be stimulated by the infection. Some early evidence of such T-lymphocyte mediated immune response has emerged from the early-stage vaccine trials. How effective is this response in defeating the virus, and for how long will it be effective? We do not know yet.
Even though the duration of protection conferred by the vaccine will not be easy to measure in a Phase 3 trial, long term follow-up studies and post-marketing surveillance will provide evidence. However, safety and efficacy must be clearly demonstrated before permitting the vaccine for widespread human use. Several thousand persons would be needed as trial participants to assess efficacy in preventing clinically recognisable Covid19 infections. Evidence from Phase 3 trials must be weighed carefully before regulatory permission is granted. Russia enacted a law this year to bypass the mandatory requirement of completing the Phase3 trial before granting regulatory approval. Will the new vaccine succeed spectacularly like the original Sputnik or will it be a dangerous gamble like the Russian Roulette? The world waits with bated breath to find out.
There are presently more than 165 vaccine candidates in the world. Of those, 31 are in different phases of human trials. It is generally expected that a fully evaluated and authorised vaccine will not be available till early next year. The Russian vaccine has yet to formally commence a Phase 3 trial, as per WHO records. Will it satisfy the global scientific community that it has passed all the tests before a public launch? Or, will an emergency authorisation be given even on incomplete evidence because of political compulsions to get the global economy back on the rails? In an epidemic with high fatality rates, such a hurry may be justified. With an infection fatality rate now estimated to be well below 1%, will a hurried trial and premature authorisation be defensible on public health grounds?
‘Vaccine Nationalism’ seems to have emerged as a major force for propelling fast track vaccine trials, untested claims of efficacy and safety with hurried launches proposed for public use. Apart from the kudos that countries seek for the strength of science and speed of development and delivery, commercial interests too play a very strong role in pushing for a podium finish in this race. There is much money to be made for the industry, though the foundational science has been public-funded. The spirit of global consultation and collaboration, needed to fast track vaccine development and trials with desired transparency and scientific rigour, are being cast aside for gaining credit and cash. It is essential that the spirit of global solidarity is resurrected along with the credibility of science. Macho-nationalism and commercial cupidity are a toxic mix that the world can do without.
If trials are conducted in haste, and a vaccine is launched without adequate proof of efficacy and safety, there is the grave danger of the vaccine failing on a stupendous scale. This applies to all countries in the vaccine race, not only to Russia. Serious collateral damage will occur because science will be discredited, proven vaccines for other diseases will be mistrusted, and public health will have a huge setback. Unless we act with wisdom, Covid19 will claim its major victims in science and public health. That damage will be iatrogenic.
The author is President, Public Health Foundation of India (PHFI) and author of Make Health in India: Reaching a Billion Plus