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.

Two strategies on anvil – Booster Dose Vs Vaccine Cocktail. Can Combination of two vaccines from different platforms enhance or prolong immunity?

Not entirely surprising

  • This should be not entirely surprising given that mixing of vaccines – has been used out for years with the Diphtheria, Tetanus, and Pertussis vaccine, among several others.
  • But here we are talking of using a combination of vaccines by a practice known as heterologous prime-boost, where two different vaccines are used as primary dose and booster dose.

Principles of Mixing Vaccines

  • Mixing should not be haphazardly or randomly done using any platforms, but should be based on understanding multiple principles.
  • What are the correlates of immunity (humoral, cell mediated or both)?
  • Which vaccines induce predominantly what kind of immune response?
  • What is the correct sequence to elicit these responses?
  • What should be the dosing interval between two prime and boost platforms?
  • Durability of the immune response.

Vaccine platforms may vary in their ability to induce antibody and T-cell response.

  • If one platform induces a predominantly antibody response, it can be followed by a platform that induces predominantly a T cell response (e.g. vector and DNA vaccines).
  • This strategy is usually used with a vector-based platform as the first shot followed by a subunit platform.
  • Worldwide, studies are under way to understand if a combination of two different vaccines can outperform two doses of the same vaccine.
  • Experts including WHO however, caution that mixing should not be randomly done but should be based on understanding scientific principles.

What prompted the Combination?

  • The idea of heterologous boosting initially emerged in Europe, when the Pfizer vaccine (First approved vaccine) was in Short Supply in UK prompting Govt to give AstraZeneca vaccine as 2nd dose booster (as it was the only vaccine available that time).
  • Countries Like Germany found AstraZeneca Vaccine to be associated with thrombotic phenomena in some young individuals. Hence, they recommended a second dose with a different platform (especially mRNA). Canada followed the same suit and on 17th June 21 officially advised mRNA-based vaccines as second dose to AstraZeneca recipients.

Initially it was the compelling factors but later on it was taken as a tool to fix low immunity

  • Interrupted supplies of a particular vaccine coupled with
    • Time bound requirements to give booster dose at 4 to 6 weeks interval
    • Urgent need to vaccinate large population to thwart rapidly rising cases of Infection with little time to wait.
    • Emerging Variants threatening to ride over the existing immunity levels prompting resurgence of cases as in UK, USA and Europe.
    • Immunocompromised individuals, transplant recipients, cancer patients showing poor antibody development with homologous prime boost prompting further studies with a Combination.

Studies in World

  • Several studies are currently underway for mixing Pfizer’s mRNA shot with AstraZeneca’s viral vector vaccine.
  • A UK-based safety study of over 800 participants, for instance, found that those who received the first dose of the AstraZeneca vaccine (known as the “prime” dose) tolerated Pfizer’s shot as their second dose (called the “boost”) quite well. The study, published in The Lancet in May, also took into account the different dosing regimens, with intervals ranging from 4 weeks. to 12 weeks.
  • This is particularly key for countries like the UK, Canada, and India, where the AstraZeneca vaccine is being administered with a gap of up to 16 weeks.
  • Beyond safety, a Spanish study found that AstraZeneca vaccinees actually benefited from taking Pfizer’s as their second dose, generating higher levels of antibodies than with shots of the same vaccine.
  • In the Philippines, researchers are studying the combination of CoronaVac, developed by Beijing’s Sinovac, with each of the six vaccines currently approved in the country.
  • Moscow-based Gamaleya Research, which developed the Sputnik V vaccine, is studying the effects of mixing it with the AstraZeneca vaccine.
  • USA based study using AstraZeneca and mRNA vaccine were able to boost immune response and neutralizing antibody titres in Immunocompromised solid organ transplant recipients.

Studies in India

Mixing Covaxin and Covishield

  • In India, an accident while administering vaccines has led to the discovery that mixing vaccines may be safe.
Vaccine Cocktails for Stronger and Longer Immunity
  • In May, 20 people in the state of Uttar Pradesh were accidentally administered Covaxin six weeks after they took Covishield, (AstraZeneca vaccine), as their first dose.
  • This alarming accident led the Indian Council of Medical Research (ICMR) to study the immune response and side effects in 18 out of the 20 people. It then compared these to a group of people who received two doses of either Covaxin or Covishield.
Vaccine Cocktails for Stronger and Longer Immunity
  • Results: Compared to the group that received doses of the same vaccines, the Covishield-Covaxin mix-and-match group had higher neutralising antibodies, according to a paper by the ICMR that is yet to be peer-reviewed.
Vaccine Cocktails for Stronger and Longer Immunity
Vaccine Cocktails for Stronger and Longer Immunity
  • Explanation: There is no easy immunological explanation in the present case. Just the data shows that heterologous vaccination triggers better antibody response
  • Drug Controller of India DGCI on 10th August 21 approved a full-length study into a heterologous prime-boost of Covaxin and Covishield – the two vaccines that make up most of India’s Covid-19 immunisation programme. The Study will be conducted in Christian Medical College, Vellore, India.

Can such a combination strategy work with Covishield and Covaxin?

  • Covishield will trigger only an anti-spike protein response (and of course anti -adenovirus response). Covaxin used as a booster in principle should boost anti-spike response further and generate a primary response against all other SARS-CoV-2 proteins which are part of the Covaxin preparation.
  • However, we really need to analyse the evidence in each of these vaccine combinations before any other recommendations can be made.

What the WHO says about mixing vaccines?

  • Risk of unauthorised mix up by public and private clinics as international borders open up, and once drug companies begin applying for full licences, vaccines will be available in private clinics and centres outside of the national immunisation programmes. This could potentially spur a dangerous trend of vaccine shopping.
  • WHO’s Soumya Swaminathan said on July 12. “It will be a chaotic situation in countries if citizens start deciding when and who will be taking a second, a third and a fourth dose.”
  • She later clarified in a tweet that public health agencies could take a call based on available data whether to allow mixing two particular vaccines or not.
  • On Aug. 10, the WHO again cautioned against the quick adoption of mixing vaccines in an interim statement. “While these studies are encouraging, they require cautious interpretation given the limited sample sizes and lack of follow up, especially related to safety data, and the uncertain relevance of immunological readouts in relation to clinical impact.”

Odds against Combination of Vaccines?

  • Companies want to sell two doses of their product, not one in combination with another company’s product.
  • From a regulatory perspective, regulators know only what companies have done – and mix-and match studies do not usually come under particular companies purview.(As per statement of Cyrus Poonawalla,chairman SII)

Initial doubts and glitches are bound to be there 

  • If proven to be safe and beneficial, the ability to mix and match to best immune response against virus could be a new tool to contain Pandemic.

CME INDIA Learning Points

  • Vaccines are not interchangeable. However, in exceptional situations, such as a contraindication to the second dose of mRNA vaccine, interchangeability may be allowed.
  • Major UK trial looking at whether Covid vaccines can be mixed with different types of jabs used for first and second doses is being expanded.
  • Combining vaccines might give broader, longer-lasting immunity against the virus and new variants of it, and offers more flexibility to vaccine rollout.

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