<ul><li>Everybody, including the Health Ministry, seems clueless on how to tackle and contain this monstrous surge. </li><li>Most experts are now convinced that this Indian variant, B.1.617, is far more contagious than earlier strains and may be resistant to existing vaccines. </li><li>Put simply, the game has changed, and a successful global rollout of current vaccines by itself is no longer a guarantee of victory. </li></ul>The relentless march of Covid’s second wave in India continues. The daily case count has gone beyond 200,000 cases per day. Everybody, including the Health Ministry, seems clueless on how to tackle and contain this monstrous surge. The nervousness of the current establishment reflects in their somewhat knee-jerk reaction to give a <a href="https://www.thequint.com/coronavirus/fast-tracking-covid-vaccines-granted-eua-in-other-nations-centre">go-ahead signal</a> to all foreign-produced COVID-19 vaccines that have been granted Emergency Use Authorization (EUA) in other countries. National Expert Group on Vaccine Administration for COVID-19 (NEGVAC) has already given <a href="https://www.livemint.com/news/india/centre-paves-way-to-have-more-foreign-produced-covid-19-vaccines-in-india-11618306108947.html">EUA</a> to a Russian viral vector vaccine Sputnik-V by Gamaleya Institute a couple of days back. Another vector vaccine, Johnson &amp; Johnson’s (JNJ’s) Adenovirus 26 (Adv26), is on the verge of getting the health ministry’s nod. Already, two Covid vaccines, Covishield and Covaxin, are being used in the ongoing program. So, soon our vaccine basket would be studded with at least four different Covid-19 vaccines. Will these vaccines be effective against the ongoing surge? Will Sputnik-V prove to be a better choice than Covishield and Covaxin? Or will the single-dose JNJ Adv26 prove to be the game-changer? To answer these queries, we need first to unveil the variant virus behind the current surge. Which variant is driving the current wave? The virus is evolving rapidly now, and the new variants have shown more transmissibility than the earlier circulating strain (D614G). In March 2021, genome sequencing of virus samples led <a href="https://www.bbc.com/news/world-asia-india-56507988">by Consortium on Genomics (INSACOG) released data</a> from 18 Indian states of 10, 787 samples found 771 cases of known variants - 736 of the UK (B.1.1.7), 34 of the South African (B.1.351) and one Brazilian (P.1). While Punjab had 336 samples positive for the UK variant, a new variant of concern (VOC) having double mutations (E484Q and L452R) in the RBD of spike protein was found in 206 samples from Maharashtra. The more <a href="https://www.hindustantimes.com/india-news/double-mutant-now-most-common-of-variantsdata-101618512310963.html">recent report</a> suggests that this “double mutation” variant, which is now termed as B.1.617, was the most common in the samples sequenced in the 60 days before April 2 at 24%, whereas the second-most commonly found variant was the UK variant, B.1.1.7, at 13% of the samples. On April 1, B.1.617 accounted for 80% of all analysed genome sequences of mutant variants sent by India to the global repository GISAID. The Indian variant B.1.617 has changed the game The above analysis shows that the main offender is B.1.617, circulating menacingly in major states of India. The new Indian variant, B.1.617, is spreading fast outside the country and is now present in at least 11 countries and 8 US states. Let us analyse this new Indian variant in detail. It has got two-point mutations - E484Q and L452R. Both point substitutions fall in the key ‘receptor binding motif’ (RBM) (438-506) region of the ‘receptor binding domain’ (RBD). Hence, they may create major changes in the viral properties. Mutations at 484 residue is a known vaccine immunity evader mutation, and the <a href="https://www.biorxiv.org/content/10.1101/2021.03.31.437925v1.full.pdf">recent study</a> on the California lineage (B.1.427/B.1.429) has found L452R also has strong immunity-evading potential. <a href="https://www.cnbc.com/2021/04/08/researchers-identify-five-new-cases-of-double-mutant-covid-variant-in-california-.html">Most experts</a> are now convinced that this Indian variant, B.1.617, is far more contagious than earlier strains and may be resistant to existing vaccines. The more worrying aspect is that the L452R, some studies show, could even make the coronavirus resistant to T cells. The other circulating variant, the UK B.1.1.7, is known for 70% higher transmissibility and 60% more lethality than its predecessor strain, but a minimal immune evasion. <div type="image" title="India vaccination" msid="82128405" hostid="261" caption="&amp;lt;p&amp;gt;India vaccination&amp;lt;/p&amp;gt;"></div> Are the current Covid vaccines capable of taking on the Indian variant, B.1.617? As stated above, India has been employing Covishield and Covaxin in a large-scale mass inoculation drive since January 16 this year. Will these vaccines be efficacious against the new variant? What about their effectiveness against the other key variant, UK’s B.1.1.7? Usually, the UK B.1.1.7 variant is not considered an immune escape lineage. Most new vaccines tried against this variant (Novavax in efficacy trial, Pfizer-BNT and Moderna vaccines in laboratory studies) have only modest reductions in efficacy or neutralization titers. However, the recently published study on this vaccine in <a href="https://thelancet.com/action/showPdf?pii=S0140-6736%2821%2900628-0">The Lancet</a> demonstrates that Covishield retains a meaningful degree of efficacy against the UK variant but has almost 9-folds reductions in neutralization titers against this variant and &gt;10 points reduction in the point estimate of efficacy than against other lineages (70·4% Vs 81·5%). Worryingly, it fails to offer any reasonable protection against <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2102214">the South Africa variant, B.1.351</a>, whereas two other vaccines, Novavax and JNJ, had reasonable protection. This needs to be remembered that the South Africa variant contains E484K point mutation (substitution), which is also found in the new Indian variant, B.1.617. Since the 484 residue is strongly associated with immune evasion, the chances of Covishield providing any significant efficacy against the symptomatic illness against the new variant is quite remote. However, it can retain reasonable protection against severe disease and death owing to good T-cell immunity. Will Covaxin be a better option? There is no efficacy data available for this vaccine against the two different variants. One small <a href="https://biorxiv.org/content/10.1101/2021.01.26.426986v2">laboratory study</a> was conducted against the UK variant B.1.1.7 isolate in January this year, and the vaccine was found to have negligible reductions in neutralization against the variant. However, there is no data on its efficacy against E484 containing variants, the key mutation in B.1.617. Will Sputnik-V be equal to the task? In <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00234-8/fulltext">its phase III trial</a>, the Sputnik-V has reported a higher efficacy than Covishield, JNJ Adv26 and CanSino’s vaccines. However, the JNJ vaccine was tried in the latter half of the pandemic in the countries where new variants were surging. Nevertheless, the <a href="https://www.medrxiv.org/content/10.1101/2021.03.31.21254660v1.full.pdf">recent reports</a> have found limited efficacy of this vaccine against SA variant, B1351 containing mutation E484K which is also there in new Indian variant. In the lab study, 8 out of 12 (75%) of serum samples from 12 recipients of the Sputnik-V vaccine failed to neutralize the virus-containing same mutations as in South Africa’s B.1.351 with E484K. The same set of sera efficiently neutralized virus-containing B.1.1.7. There are other drawbacks also like the need for storage at low temperature though recently the manufacturers have claimed that it can be stored at 2-80 temperature and <a href="https://science.thewire.in/health/covishield-what-we-need-to-know-to-understand-the-safety-of-viral-vector-vaccines/">potentially serious rare side-effects</a> associated with other viral vector vaccines. The safety data of the vaccine are not yet fully revealed. Few experts are still sceptical about their claim of 91.6% efficacy and find their data fudgy. What about other Covid-19 vaccines? Two other vaccines, JNJ’s vector-based and Novavax’s protein subunit vaccine, are also in the pipeline for introduction in India. Both are being manufactured here also. Both these vaccines have shown reasonable protection against SA variant having E484K mutation, a key immune evader and related to the Indian B.1.617 variant in an efficacy trial in SA (Efficacy: JNJ=57-64 % and Novavax=49-60 %) (Table 1). The other advantage of JNJ is a single-dose administration. Novavax is extremely safe, being free from the rare adverse events of vector vaccines. Though they are not yet tried against the new Indian variant, going by their efficacy against E484K mutation, they are supposed to provide better protection against this variant than both Covishield and Sputnik-V. Table I. Efficacy of different Covid vaccines against key variants <img src="https://lh4.googleusercontent.com/MC1GTZJ-fgiopxfMUYiQulhHzDNNHfnSsKis4tucUGS0DJkJNGoV48Zi8bOdxuAB1j6kGkmq8hrPyPr5AxC-qC9R_1OnYJbp685bJ9KuRT58O8HV8Td7y8dF_iii59Gz1Np2MAu-y3i6EYOaJQ" /> Source: Dr Vipin Vashishtha What is needed? We are in a race against time to get global transmission rates low enough to prevent the emergence and spread of new variants. Put simply, the game has changed, and a successful global rollout of current vaccines by itself is no longer a guarantee of victory. Still, large scale vaccination may count provided we use them judiciously. First, we need to do extensive genomic sequencing of the circulating variant to ascertain the exact proportional burden of two major variants, B.1.617 and B.1.1.7. If the B.1.617 causes the major chunk of cases, our choice of vaccines shall change as stated above. Next, there is an urgent need to study the protective efficacy of the employed Covid vaccines in different categories of Covid positive individuals who had already received these vaccines. Small field studies of these vaccines against the two key variants can also be conducted. Even if these studies are not feasible, laboratory-based neutralization studies with live or pseudo-viruses having ‘double mutants’ can be attempted. There is a definite need for a booster dose of most Covid vaccines. Pfizer, Moderna, and JNJ are already contemplating the 3rd dose within one year of the primary course. Other vaccine developers of Covishield, Sputnik and Novavax should also follow suit, particularly against new variants, B.1.351 and B.1.617. We need to be judicious while planning vaccination drives. It should have a significant impact at the population level and should counter any future surge. I would personally bet on Novavax. This highly efficacious vaccine has already shown better efficacy against 484 containing variants, free from the rare serious adverse events of viral vector vaccines and based on a time-tested platform. Fortunately, this vaccine is being produced in India, and the company has already committed at least one billion doses to India. Ideally, the public health policies should be guided by the science and the evidence, not by the programmatic feasibility. There is no point inoculating billion people with a jab that may not accord requisite protection against the offender. 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OPINION: “I would bet on Novovax,” a doctor’s take on how to make the COVID-19 vaccine jabs more effective

<ul><li>At the current rate (0.67 million per day), it will take at least 5.6 years to vaccinate the entire population with a single dose.</li><li>India needs to ban the export of vaccines manufactured in India to ramp-up vaccine distribution.</li><li>A massive effort is needed to vaccinate at least 10 million people per day that may have some dent in the virus’s ongoing intense transmission.</li></ul> The fact that the second wave of Covid-19 pandemic has arrived in India can neither be denied nor overlooked. And the new wave seems to be more severe both in terms of infectivity and lethality if one goes by the initial data gathered from the states severely affected by this recent surge. More than 55,000 cases and 250 deaths have been<a href="https://www.businessinsider.in/india/news/india-reports-59118-new-covid-19-cases-in-last-24-hours-highest-single-spike-since-october-last-year/articleshow/81701772.cms"> reported</a> as of March 26 — the highest so far this year. Why the second surge? Opinions may be divided on the exact reason behind this resurgence. Still, as more and more data are emanating, it seems the advent of the new and more infectious variants, mainly the UK variant having N501Y substitution and 69/70 deletion, may be the main reason behind these outbreaks in a few states. The limited gene sequencing data have already pointed toward the presence of two distinct variants, the UK and South African in Maharashtra and Punjab, the two most severely affected states. The other reason could be laxity by both the Government and public in adhering to the non-pharmacological mitigation measures like masking, social distancing, avoiding gathering, etc. Another important reason could be the secular changes in the epidemiology of the SARS-CoV-2 virus since the first 3-4 months of the year favours the dissemination of respiratory viruses in some Indian states like Maharashtra, Gujarat, etc. One should remember that globally also, many waves of Covid-19 outbreaks have been observed. What impact did Covid vaccines have? Now, it brings us to the critical question. What role did the Covid vaccines have in India’s ongoing fight with the virus? India gave emergency use authorisation to two Covid vaccines — Covishield and Covaxin — in the first week of January 2021 and started the first inoculation phase from 16th January. So far,<a href="https://news.google.com/covid19/map?hl=en-GB&amp;mid=%2Fm%2F03rk0&amp;state=7&amp;gl=GB&amp;ceid=GB%3Aen"> around</a> 50 million doses have been administered, and 8 million people have received both doses. At the current rate (0.67 million per day), it will take at least 5.6 years to vaccinate the entire population with a single dose. Even if we add the already infected (i.e., 12 million) to the tally, 4.4 years would be needed to vaccinate everyone. We all know that the current threshold to achieve herd immunity is 70%, provided vaccines offer 100% protection and prevent asymptomatic transmission. Also, this estimate is based on the old circulation variant (D614G). Even this target (70%) would be reached in four years even with a single dose, and more than 20 years with the current pace. This means the impact of vaccination would be minimal until we cover a sizable proportion of our population. And by that time, the pandemic would have run its course. So, in all probability, the role of mass-scale vaccination would become redundant. Globally also barring one country,<a href="https://www.aljazeera.com/news/2021/3/25/half-of-israelis-fully-vaccinated-palestinians-lag"> Israel</a>, that has vaccinated more than 51% of its population with two doses, no other country has shown significant Covid vaccination. In the UK, where the new variant has caused a massive second wave in the last quarter of 2020, it was a strict lockdown that had maximum impact on the pace of the pandemic, though vaccination had some effect on the older population. Similarly, in the US, the virus’s natural epidemiological variation led to the waning of the third wave of their epidemic. However, one can ascribe the minimal impact of mass vaccination in large countries like the UK and US with a partial vaccination of the susceptible population. The most glaring example of the failure of large-scale vaccination is offered by<a href="https://www.nbcnews.com/news/latino/chile-critical-grip-second-covid-wave-one-best-vaccination-rates-rcna505"> Chile</a>, where despite vaccinating one-third of its people with a single dose and lying in the top three countries as far as vaccination per capita is concerned, it suffered another massive surge. <div type="image" title="Representative image." msid="81720961" hostid="261" caption="&amp;lt;p&amp;gt;Representative image.&amp;lt;/p&amp;gt;"></div> How to make vaccines relevant to our fight against the Covid pandemic? So, will Covid vaccines fail to curb the ongoing pandemic? No, it depends on how judiciously we employ them. There is an intense competition between the pace of vaccination and the steady speed of virus spread. So far, the virus seems to be having the upper hand, and it is propelled by the assistance offered by its ongoing evolutions into more efficient forms. As far as India, the second-most-populous country in the world, is concerned, it seems handicapped by its inability to vaccinate quickly. Following measures may help to make vaccinations count as an effective intervention against the ongoing pandemic rather than as a redundant exercise: 1. Ramping up considerably the pace of vaccination: As described above, the current vaccination rate is sluggish. A massive effort is needed to vaccinate at least 10 million people per day that may have some dent in the virus’s ongoing intense transmission. At this rate, we can vaccinate a sizeable chunk of our population within 3-4 months that may halt the ongoing transmission. India can do this -- during the polio supplementary immunisation activities, India had vaccinated around<a href="https://www.bbc.co.uk/news/world-asia-india-25708715"> 170 million children</a> during a round of vaccination. The vaccination at the current pace will lead to significant immunity gaps that may facilitate viral mutations. 2. Ban on export of vaccines manufactured in India: A critical hindrance to the rapid ramp-up of vaccine distribution would be the limited supply of vaccines. India may need at least 1.5 billion doses for its domestic use. On March 25th, India put a temporary <a href="https://www.bbc.com/news/world-asia-india-56513371">hold </a>on all major exports of two indigenously produced vaccines. This is a step in the right direction considering ongoing intense viral transmission. However, another important vaccine, Covovax, originally developed by Novavax and produced here by the Serum Institute of India, is also needed to be prioritised for domestic use, and export should be deferred. This candidate has proved to have excellent efficacy and ease of production with tremendous scalability. Owing to these essential virtues, this candidate is the key to vaccinating the entire globe, not the mRNA or vector-based vaccines. 3. Need to fast-track the regulatory approval of Covid vaccines: Currently, Indian regulators have made it mandatory to conduct bridging studies in India for emergency use authorisation of even a proven product. Though this may add a certain value, this may prove to delay the vaccines’ roll-out amid an intense outbreak. Those vaccines that have already proven their efficacy amongst different populations need to provide a waiver. For example, few key vaccines like Novavax’s protein sub-unit, Sputnik-V and Janssen’s Ad26 vector vaccines, are being produced here by some Indian companies. All these vaccines have proven their efficacy globally, and two of them are in use in many countries. They should be made available for domestic use. 4. Rescheduling the administration schedule: Recently, the government of India announced a prolonged time interval between the first and second<a href="https://qz.com/india/1987681/india-increases-covishield-dose-gap-amid-delayed-shipments-to-uk/"> dose</a> of the Covishield vaccine from 4 weeks to 6-8 weeks. However, the<a href="https://www.thehindubusinessline.com/news/science/covishield-is-813-efficacious-if-two-doses-administered-12-weeks-apart-lancet-study/article34025087.ece"> recent trial</a> of the Covishield demonstrates that a 12 weeks interval provides a higher efficacy (up to 81%) than at 6-8 weeks (60-64%). Furthermore, even single-dose protection may last up to 12 weeks with a reasonably good efficacy (76%). Similarly, the dosing schedule of inactivated vaccine, Covaxin, can be prolonged to 8 weeks since immunologically, a higher interval between two doses provides better immunity. Hence, it would be more fruitful to delay the second dose administration to enable a massive inoculation drive in the shortest possible time. 5. Abolish prioritisation for vaccination: The current government strategy, which is based on the WHO directive, is providing hindrance to rapid vaccination of the entire susceptible population. Covid immunisation should be made accessible for all on a war footing level. 6. Spread vaccine delivery points: Though the existing government distribution system can vaccinate 10 million individuals per day, nevertheless expanding the vaccine delivery booths at certain entry points like at airports, bus, railway stations, etc., may expedite this drive. Even mobile vaccine booths can be developed across the country. 7. Speeding up the genetic sequencing: Currently, only a few thousand samples have been sequenced genetically. Only a few hundred samples are taken up for genetic sequencing in a few large states like UP. Following the confirmation of a few variants in the country, there is an urgent need to ramp up the sequencing and study the vaccine efficacy against these emerging variants. The above-listed measures may help deliver Covid vaccines to a significant proportion of the population in the shortest possible time. To vaccinate the entire country over a few years may not serve any purpose. We need to utilise vaccines' availability to serve the purpose for which they were produced in a record time to end this pandemic. Dr. Vipin M. Vashishtha is the former convener at the Indian Academy of Pediatrics (IAP) Committee on Immunisation, and a Pediatrician at Mangla Hospital and Research Centre in Bijnor, Uttar Pradesh SEE ALSO: <a href="https://www.businessinsider.in/stock-market/news/barbeque-nation-ipo-gets-subscribed-almost-6-times-and-allotment-will-announced-on-1st-april/articleshow/81707826.cms" data-type="tilCustomLink" target="_blank">Indian dining chain Barbeque Nation’s IPO gets subscribed almost 6 times</a> <a href="https://www.businessinsider.in/business/news/ever-given-the-ship-blocking-the-suez-canal-is-costing-billions-of-dollars-for-people-around-the-world/articleshow/81708146.cms" data-type="tilCustomLink" target="_blank">Ever Given, the ship blocking the Suez Canal, is costing billions of dollars for people around the world</a> <meta content="cms.next" name="cmsei" />

Dr. Vipin M. Vashishtha

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OPINION: “I would bet on Novovax,” a doctor’s take on how to make the COVID-19 vaccine jabs more effective

Dr. Vipin M. Vashishtha

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