CME INDIA Presentation by Dr. S. K. Gupta, MD (Med), FICP, CFM (France) Clinical Asst. Professor GS Medical College, CCSU, Uttar Pradesh, India. Visiting Consultant, Max Super Specialty Hospital, New Delhi.

Vaccination is our best defense against COVID-19, including the circulating variants, and shortening the length of time between completion of a primary series and a booster dose may help reduce waning immunity – Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, USA.

Mix and Match

• Should the 3rd dose booster be of same vaccine as primary series or a different one?
• Mix and Match (heterogeneous Third dose booster after primary series)
• As per Government of India: There will be no mix-and-match of vaccines for those eligible to get a ‘precautionary’ third dose.
• This means individuals who received two doses of the Serum Institute’s Covishield will get the same vaccine this time, and those who got Bharat Biotech’s Covaxin will get a third jab of that vaccine.

Why some health care workers are pitching for a third dose booster with different vaccine?

• CovBoost Trial (1) A double blind excellent study funded by UK Vaccine Taskforce and National Institute for Health Research published on 2nd December 2021 found that third dose booster by a different vaccine boosted the immunity to much higher levels especially after primary vaccination with Killed vaccine or Vector vaccine (Chadox1).
• As per the study all vaccines boosted the immunity after Chadox1 but  there were marked differences in response e.g. AstraZenaca used as booster increased levels of Neutralizing antibodies to 2.5 times while Novavax vaccine raised it to 6.2 times. Inactivated Virus vaccine Valneva from Europe boosted antibodies 2.04 times.
• Note: Covboost trial did not include Covaxin. But another inactivated Vaccine Valneva manufactured in Europe.
• See Input from Dr Rajeev Jayadevan, Chochin:

“This has important implications while planning vaccine strategies, and might explain the rather muted antibody response in the UK paper that compared a menu of boosters (only 2x in some) The 28x spike with mRNA booster could be from too small a gap between the 1st doses.”

Modified from Ref 1, Courtsey Lancet

It is pertinent to know that study was done in UK and results may vary in different populations

• UK COMCOV trial was heterologous prime boost trial related to second dose of vaccine. It  demonstrated that a heterologous prime-boost schedule can be more immunogenic than a homologous schedule, albeit with increased reactogenicity in some combinations. (2)

Why Govt. not offering Novavax as third Dose booster?

• Despite huge availability of doses of Novavax (Covovax) in India, why the Govt. advisers choose to stick with homologous booster could be something difficult to understand. One possible reason could be absence of booster dose trials with Covovax in Indian Subsets. However, going by study results of CovBoost trial Covovax could have been a wonderful choice as a third dose booster.

WHO stand on Mix and Match of Novavax

• WHO accepts two heterologous doses of its COVID-19 vaccines as a complete primary series. However, there is limited evidence available on the use of Novavax (NVX-CoV2373) in a heterologous schedule.

Is Novavax Approved?

• Yes, it is Approved for Emergency use EUL  by WHO, European Medical Agency and DCGA India. FDA has not Approved Novavax as yet.

What other countries offering as Third Dose Booster? Mix and Match or same/similar vaccine?

• UK
  • To all more than 18 yr. plus.
  • Booster dose at least 3 months after the 2nd dose.
  • Most people are offered a booster dose of the Pfizer/BioNTech or Moderna vaccine irrespective of primary vaccines.
  • Some people may be offered a booster dose of the Oxford/AstraZeneca vaccine if they cannot have the Pfizer/BioNTech or Moderna vaccine.
• USA
  • Booster to all more than 18 yr. of age.
  • 6 months after the primary series of Pfizer/Moderna.
  • Same vaccine platform.
  • If more than 18 yrs. and Johnson vaccine was taken as primary vaccine, then booster offered 2mths after and would be from either Pfizer/Moderna.
• Switzerland
  • Using same vaccine as Third dose booster as primary Vaccine.
• Spain
  • Spain had administered 9.76 million booster shots  until 16 December 21.

• So, most of developed countries are offering Pfizer or Moderna vaccine as third dose booster which remains the same vaccine as the primary series in most cases, except in people who received single dose J&J vaccine (Ad26) or two sides of Chadox1 vaccine.
• No country has yet mounted Novavax as third dose booster despite evidence from CovBoost trial, not even UK where the trial was done. It continues to offer Chadox1 to some people who received it earlier as well.

Time interval controversy with Third Dose Booster. What should be the optimal desired interval of Third Dose Booster?

• India is offering third dose booster after Nine months (39 wks.) of second dose, while in USA cut off period is 6 months, Brazil is giving it after 5 months and in UK it is 3 months. 
• France, on 24th December 21, recommended booster vaccination after three months – reducing the guideline of five months to better fight the Omicron variant.

How to decide the interval of third dose booster?

• Studies have shown that the effectiveness falls to just 34 percent four months after vaccination with the Pfizer vaccine but the efficacy rose to 75 percent two weeks after a booster dose.
• It is noteworthy that different vaccines will have different duration of effectiveness as measured by neutralizing antibody titres. So Govts ought to decide the interval of third dose booster based on waning immunity after second dose. Other important deciding factors could be availability of doses.

For India, the decision of using same vaccine rather than mix and match of Covaxin and Covishield could have been driven by following factors:

• Absence of Indian trial data on mix and match using Covishield and Covaxin.
• Limitation of dose supply of Covaxin. HCW FLW constitute 3 crore people and 60 yr. plus with comorbidities people constitute another 2.7 Crore and ninety percent of them having received Covishield in primary series could have become eligible for Covaxin in case mix and match allowed. Covaxin presently being committed for 15 to 18yr age group already had a booked demand of 7.3 crore doses. Seeing current and future supply constraints of Covaxin it was in the best interest of the nation to follow same Third Dose Booster.
• It is noteworthy that Covaxin is manufactured in BSL4 labs and there are very few labs in world fulfilling the BSL4 criteria. Let’s not get worried.

Cell Mediated Immunity comes to Rescue?

• As stated earlier, the concept of Third dose booster is primarily driven by Neutralizing Antibody titres but vaccines remain effective despite decreasing Antibody titres. Most of us tend to forget the role of Cell mediated immunity just because there are no commercially available tests to measure the same.
• T-cell immunity not affected by Spike protein mutations in Virus.
• T-cells are important in controlling disease severity. T-cell activity appears minimally affected by spike antigen mutations and responses remain effective even against variants of concern, even though neutralising antibody levels are reduced. As per the studies, although neutralising antibody titres after mRNA vaccination may be higher compared to adenovirus vector vaccines, there are much smaller differences in T-cell responses.

Are there any trials with Covaxin as third dose booster in India?

• Yes, A phase 2, double-blind, randomised controlled trial demonstrated long-term safety of Covaxin vaccine 6 months after the primary series.
• Analysis showed that six months after a two-dose BBV152 vaccination series, cell-mediated immunity and neutralising antibodies to both homologous (D614G) and heterologous strains (Alpha, Beta, Delta, and Delta plus) persisted above baseline, although the magnitude of the responses had declined.
• Furthermore, neutralising antibodies against homologous and heterologous SARS-CoV-2 variants increased 19 to 265-fold after a third vaccination. Booster by Covaxin (BBV152) vaccination is safe and may be necessary to ensure persistent immunity to prevent breakthrough infections.(3)

Booster dose trial with AstraZeneca?

• Booster dose Trial from Chadox1 (Covishield).
• A sub analysis from the COV001 and COV002 trials demonstrated that a third dose of Vaxzevria given at least six months after a second dose boosted antibody levels six-fold and maintained T-cell response. A third dose also resulted in higher neutralising activity against the Alpha, Beta, and Delta variants, compared with a two-dose regimen. In the trial, the third dose of Vaxzevria was less reactogenic than the first dose
• In addition, the COV-BOOST trial showed that a third dose booster of Vaxzevria induced significantly higher immune responses compared with controls against the Delta variant and original strain following a primary vaccine series of Vaxzevria or Pfizer BioNtech (BNT162b2).(4)

Will the same Third dose booster as offered by Govt be effective?

• Yes. Govt has moved a step forward to offer the third dose booster. There could be controversies regarding timing, type of vaccine, immunogenicity but it is safe and should be effective as immunity booster.
• Decrease in cases of Breakthrough infection among HCW in coming days will be the real test of Efficacy of any Booster.

Nevertheless, it will serve as wonderful Moral Booster

• If you are too much trial driven and evidence savvy, please don’t forget that even placebos have an efficacy of more than 33%.
• Also note that taking the same booster makes you eligible to get Certificate of 3rd Dose Booster, which might be useful in times to come.
• Happy Boosting.

CME INDIA Learning Points

Boosters vs. Third Doses

• A third dose is for people who are moderately or severely immune-compromised; their original immune response from the first 2 doses may not have been strong enough, so a third dose is recommended as part of their primary vaccine series.
• A booster shot is an additional dose of vaccine given after the protection provided by the original shot(s) has begun to weaken over time. A booster is intended to help people maintain immunity for a longer period of time.
• Precautionary Dose started by Govt of INDIA (5)
  • ‘COVID-19 Working Group of National Technical Advisory Group on Immunization (NTAGI)’ as well as of ‘Standing Technical Scientific Committee (STSC)’ of NTAGI, it has now been decided to further refine the scientific prioritization & as a matter of abundant precaution to provide “Precaution Dose” of COVID-19 vaccination to HCWs, FLWs & 60+ population with comorbidities:
    • Date of Commencement: 10th January 2022.
    • Vaccine to be given: It will depend upon the vaccine the eligible person has taken previously. The person who has taken two doses of Covaxin previously will be eligible for precaution dose of Covaxin only and the person with two doses of Covishield will be eligible for precaution dose of Covishield only.
    • Eligibility Criteria: ➢ Health Care Workers (HCWs) ➢ Front Line Workers (FLWs) ➢ 60+ Population with comorbidities o are expected to obtain the advice of their doctor before deciding to avail the precaution dose.
  • After completion of Nine (9) months or Thirty-nine (39) weeks from the date of administration of 2nd Dose of COVID-19 Vaccine as recorded in Co-WIN system.
• Just recovered from COVID, already taken 2 doses, to give booster or not?
  • At present, persons who have recovered from COVID-19 and were fully vaccinated before their infection, do not need a booster dose.
  • Recovered persons who were unvaccinated, or partially vaccinated before their infection, should receive at least 3 months after infection to reduce their risk of reinfection, as part of their primary series vaccination. No additional booster dose is recommended.

CME INDIA Tail Piece (6,7)

• An analysis of data by researchers Edouard Mathieu and Max Roser of Our World in Data, a data research portal, showed that in Switzerland, the weekly death rate per 10,000 people is 8.63 in the case of unvaccinated while it is 0.74 in the case of the vaccinated population as on December 4, 2021. This suggests that vaccines are working and providing long-term immunity.
• Researchers in Chile found that the weekly death rate in unvaccinated is 3.15, while that in the vaccinated is 1.99. The country started administering booster shots in August and the weekly death rate in this population is 0.23.
• Eye Opener:

• Want to explore more? Read Fabulous article by Dr Rajeev Jayadevan, how not to be fooled while reading research studies. See link – Ref 8

References:

1. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02717-3/fulltext
2. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01694-9/fulltext
3. https://www.medrxiv.org/content/10.1101/2022.01.05.22268777v1
4. https://www.astrazeneca.com/media-centre/press-releases/2021/vaxzevria-significantly-boosted-antibody-levels-against-omicron.html#!
5. GOI/D.O.No 2058150/Imm.06.01.2022 and 04.01.2022
6. http://www.millenniumpost.in/opinion/science-of-booster-vaccine-462520
7. https://ourworldindata.org/covid-deaths-by-vaccination
8. https://www.onmanorama.com/lifestyle/health/2022/01/09/how-not-to-be-fooled-reading-research-studies.html

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