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

• Everybody, including the Health Ministry, seems clueless on how to tackle and contain this monstrous surge.
• 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.
• Put simply, the game has changed, and a successful global rollout of current vaccines by itself is no longer a guarantee of victory.

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 go-ahead signal 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 EUA to a Russian viral vector vaccine Sputnik-V by Gamaleya Institute a couple of days back. Another vector vaccine, Johnson & 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 by Consortium on Genomics (INSACOG) released data 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 recent report 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 recent study on the California lineage (B.1.427/B.1.429) has found L452R also has strong immunity-evading potential.

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. 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.



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 The Lancet 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 >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 the South Africa variant, B.1.351, 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 laboratory study 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 its phase III trial, 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 recent reports 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 potentially serious rare side-effects 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



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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