13 October 2021 Episode 181 Follow-up on Sputnik V

Wed, 10/13/2021 - 12:46

Dear colleagues,

A colleague asked about the long-term effectiveness of the Russian Sputnik V vaccine and that is an interesting question indeed.  I will first refer to a previous episode 136 of MAY 4th , in which I discussed the results of the phase 3 trial and the early controversy on this vaccine.  You find the text as Ep 181-1 (with the link to all the “early” papers). 

Just briefly:  Sputnik V combines two adenoviral vectors, derived from human viruses: Ad 26 as “prime” and Ad 5 as “boost”.  Both carry the genetic code for “native” SARS-CoV-2 Spike protein.  Clearly, Ad 26 is the same vector also used in the Janssen vaccine, but they have inserted the S protein in the “prefusion” conformation, which Janssen showed to elicit superior immune responses (Ep 181-2).  On the other hand, Janssen applies only 1 dose, while Sputnik adds an “heterologous” Adeno 5 booster.  The use of two different vectors in Sputnik is designed to reduce the chance of the body developing antibodies to Ad after the first dose, which could make the second dose ineffective.

According to the original phase 3 data:

  • Ep 181-3: Sputnik was tested in Russia between 7 Sept and 24 Nov 2020, when the Wuhan strain with D614G mutation was circulating.  Sputnik’s overall efficacy against symptomatic PCR confirmed COVID was 91.6 % across al age groups and 100 % against moderate to severe COVID.  Thus, at first view, rather comparable with the mRNA vaccines       
  • Ep 181-4: Janssen was tested in North and South-America, as well South-Africa between 21 Sept 2020 and 22 January 2021,  when several variants were already circulating.  Overall efficacy was 66.9 % against moderate-to-severe COVID and 76.7 % against severe-critical COVID.  In South-Africa however (with the beta variant getting dominant) protection against moderate-severe COVID was only 52 % and 73 % against severe-critical COVID.  

Interpretation and criticism

Ep 181-5: While the difference in efficacy between both vaccines, expressed as “relative risk” (vaccinated/control) seems very big,  Montastruc et al argue that this parameter is of limited clinical interest,  because it fails to take into account baseline risks and tend to exaggerate the positive results of studies.   The main parameter they propose is “absolute risk reduction” (ARR), which, in fact is rather comparable for the different COVID vaccine, but clearly lower than for Influenza or EBOLA vaccines.  (See Table 1)

Ep 181-6: The conclusions of a trial, however expressed, are only valid if the methodology is sound.  In the Lancet of 22 May, an international panel of Western experts expressed a lot of concerns about (1) the incomplete transparency of the data; (2) several late changes, irregularities or inconsistencies in the protocol; (3) the statistical analysis.  The answer of the (Russian) authors, in my opinion, is rather evasive. 

Contrasting reports on immune responses against variants of concern and real world efficacy

Enthusiastic Russian follow-up

Ep 181-8:  A Russian team (including the authors of the trial) in Vaccine MDPI (July) evaluated the virus neutralizing activity (VNA)  of sera from Sputnik vaccinated subjects against a range of SARS-COV-2, using a “pseudoviral” approach (which looks quite standard). 

They find

  • No significant differences in VNA against B.1.1.7 (alpha), B.1.617.3, and local genetic lineages B.1.1.141 (T385I), B.1.1.317 (S477N, A522S) with RBD mutations.
  • For the B.1.351 (beta), P.1 (gamma), and B.1.617.2 (delta)statistically significant 3.1-, 2.8-, and 2.5-fold, respectively, VNA reduction was observed. Notably, this decrease is lower than reported in publications for other vaccines.

However:

  • A direct comparative study with sera from other vaccines is necessary for a final conclusion.   
  • There was no information on the vaccinees: e.g. how much time since vaccination, age etc.

Ep 181-9: A press communication in April claims over 97 % efficacy in the general Russian population:

Data from 3.8 million Russians who received both components of Sputnik V from 5 December last year to 31March this year, … revealed an infection rate of 0.027% starting from the 35th day on administering the first dose. Furthermore, the disease incidence among unvaccinated adults was 1.1% from the 35th day after launching mas vaccination in the country. 

As far as I can see, these claims have never been formally published.

Ep181-10: A BMJ comment by Chris Banjaruk from Belfast, however, provides a lot of criticism both from scientist and the European Commission.  In addition, there is also lack of trust within Russia, because of the very quick development and approval:  The rollout may be hampered by scepticism about Sputnik V among the Russian public—an online survey of 1600 Russians conducted by the Moscow Times found that 60% were opposed to receiving it. The swift approval has also prompted wariness among some Russian doctors.  

Clearly, these are remarks are those from Dr. Banjaruk.

 

Rather positive data from Argentina

Ep 186-11:  An Argentinean study in health care workers (Rossi et al, in Cell Reports Medicine) shows a high seroconversion rate after Sputnik, even in people over 60 years (> 89 %)  in a rather small cohort of vaccinees, with > 90 % showed neutralization activity in a pseudovirus assay.  There is also a very strong increase of neutralization in previously infected subjects, who subsequently received the vaccine (as is the case with other COVID vaccines)

However, as the authors state:

  • An efficacy study is  necessary to assess vaccine protection in the population and to define correlates with antibody titers.
  • In addition, follow-up studies are needed to evaluate the duration of the immune response.   

 

Ep 186-12: A mixed US-Argentinian team(Ikegama et al.  Nature Comm) confirms that sera from (well-characterized) Sputnik V recipients have similar neutralizing activity against wild-type and alpha, but they find a more profound reduction against beta (as well as against viruses with the crucial E484K mutation). The difference is in the assay, which features a more optimized infection of the target cells.

Ep 186-13: A more optimistic view from Argentina (Gonzales Lopez Ledesma in medRxiv): a large team from Buenos Aires shows in 88 Sputnik vaccinees that Spike-specific antibodies wane over 4-6 months (Fig 1 p. 5), but neutralization activity is rather stable in absolute terms (Fig 1 D) and actually relatively improves against variants of concern (Fig 2 p. 7). 

  • 42 days after vaccination, neutralization against beta, gamma and delta is resp. 19, 14 and 5 times lower than against Wuhan
  • 120 days post vaccination the reduction is only resp. 10, 4 and 3.4 times.

This observation is taken as a sign of the “maturation” of the B cell response and has been described also after natural infection and for other vaccines.      

 

Ep 181-14: Another optimistic report from Argentina on high effectiveness of the first component of the Sputnik V only (hence the Ad26 S prime) in a large population (over 40,000 individuals) between 60 and 79 years old, followed up during 21-83 days after vaccination.  It is a retrospective study with a similar number of unvaccinated controls, matched for age, gender and comorbidities. As can be seen in Table 2 the efficacy against infection, hospitalization and death is high and in fact very comparable to other vaccines:  preventing symptomatic infection was between 51-76%, hospitalisations 66_9-91%, and deaths 85-91% for Pfizer-BioNTech, Astra-Zeneca, Moderna and Janssen vaccines

 

Sobering data from Mongolia

Ep 181-15 A and B: Two preprints from Mongolia, where 4 different vaccines were used and, despite a high vaccination rate, a new wave of infection was noted in June-July 2021, which was largely due to the alpha variant.. 

In A Fig 1 A clearly shows that the order of capacity to “neutralize” (in the ACE2 blocking assay) by sera from vaccinees against all variants is always Pfizer > Astra-Zeneca > Sputnik V > Sinopharm

 

Different overall appreciation in scientific reviews

Ep 181-16: A comment in Nature on July 15th by Bianca Nogrady (a freelance science journalist) provides a rather positive picture under the title: MOUNTING EVIDENCE SUGGESTS SPUTNIK COVID VACCINE IS SAFE AND EFFECTIVE.  Amongst other data, Ep 181-14 is quoted in favor of efficacy.  According to the original trials, but also to small studies independent studies, side effects seem remarkably mild, as compared to Astra-Zeneca and Janssen. 

Especially remarkable is the absence of reports on the much feared “thrombosis and thrombocytopenia syndrome” (a very rare but serious complication of both Astra-Zeneca and Janssen). Some of the interviewees in this paper doubt the capacity of Russian and other authorities (in the 70 countries were Sputnik is being used) to detect this complication….

 

Ep 181-17: Cazzola (Italy) in Respiratory Medicine (Aug 2021) reviews the various aspects:

Pros: besides the reported rather good efficacy and safety, it has several other advantages: low cost, stable at 4 °C  and the technology is made available to low income countries.  

Cons: The concerns about errors and inconsistency in the trials and the doubts about the activity against different variants have already been discussed.  In addition, there is some concern about the use of an Adeno5 vector in populations with high levels of Adeno5-specific antibodies and high risk for HIV acquisition, as the (in)famous HIV STEP trial has shown that such populations, after Ad5 vaccination could indeed get HIV more easy. 

 

Dismissive attitude of  various regulators

Cazzola reminds of the Brazilian doubts (already partly discussed in Ep 136):

  • A Brazilian study reported that the Ad5 vector is not inactivated and is capable of replication. Sputnik V formed plaques on cultured lung epithelial cells likely due to Ad5 infection, likely because still active E1 (should have been  deleted in these  “non-replication competent adenovectors”).  
  • Later, the Brazilian authorities granted the authorisation with conditions

Ep 181-18 A and B: Already in March 2021, the European Medicine Agency (EMA) started a “rolling review” on Sputnik V, but no progress has been made. According to a recent Reuters paper: Russia has repeatedly delayed inspections by EMA necessary for the certification of its Sputnik V COVID-19,vaccine in the European Union, the EU's ambassador to Moscow was quoted on Sept 17.  

Ep 181-19: According to the Washington Post of Sept 28, the US will not accept a vaccination by Sputnik V as evidence of immunity against COVID, implying severe travel restrictions not only for Russians, but for people from many other countries, who received Sputnik vaccines

Ep 181-20:  According to Euronews on Sept 20th, the World Health Organization (WHO) has suspended the approval process for Russia's Sputnik V COVID vaccine. A regional WHO official said the manufacturing process of the jab had not met the necessary standards.

 

Conclusion

The Sputnik vaccine may have an efficacy that is comparable with other adenoviral vaccines, but there are issues with transparency  on the production process and on the trial data, which still frustrate international regulators.  

 

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