Can a mix-and-match COVID-19 vaccine approach hold a promise of boosting immune response?

Some countries have started offering mRNA alternatives to AstraZeneca as a second shot because of rare blood clots to boost immune response. However, clinical trials on mixing different types of vaccines are still ongoing. 

Author: Sara Maria Majernikova
Editor: Daniel Jacobson
Artist: Sophie Maho Chan

The vast majority of vaccines developed to protect us against coronavirus require two separate doses. However, is it absolutely necessary that the same vaccine be applied on both occasions?

The World Health Organisation (WHO) is convinced that by administering multiple different vaccines, which expose the immune system to various parts of pathogens, the body becomes trained to recognize different parts of the invader, meaning the immune system becomes more effective at defending the human body against them. For instance, viral vector vaccines are well-equipped to stimulate a part of the immune response which helps to generate an army of “killer T-cells” to protect the body against an invading virus. Other kinds of vaccines are thought to twist more heavily towards prompting the creation of antibodies to combat the attacking virus. Both immune system responses are helpful and vital. Thus, scientists theorize that combining them could hold a bigger potential than either one of them alone. 

The approach, known among scientists as heterologous prime-boost, has been explored by Julia Rühl and colleagues who conducted rodent experiments to develop vaccines against Ebola, tuberculosis and even cancers associated with the Epstein-Barr virus. Mouse experiments like these have been applied for other coronaviruses in the past, such as the original Severe Acute Respiratory Syndrome (SARS) related virus and the coronavirus causing Middle East Respiratory Syndrome (MERS). In line with that, the WHO suggests that one particular area where the mix-and-match approach brings the most hope is in the fight against HIV. This is not the first-time scientists have investigated something appearing to be a very unconventional way of vaccine dosing, and it is not necessarily something to fear. 

In parallel to preventing infection thanks to the vaccination, COVID-19 is an infectious disease caused by a newly discovered coronavirus, namely SARS-CoV-2. WHO informs the cumulative number of cases reported globally now exceeds 183 million and the number of deaths is almost 4 million. So far, the WHO has evaluated the following vaccines against COVID-19 have met the necessary criteria for safety and efficacy, namely the AstraZeneca/Oxford vaccine, Johnson and Johnson (J&J), Moderna, Pfizer/BionTech, Sinopharm and Sinovac. The only varying factors are the vaccine type (either vector, mRNA, or inactivated virus), the efficacy on the circulating variants, likelihood of serious side-effects and the number of required shots.  

According to The Conversation, vaccination is the safest way to gain immunity to the coronavirus, and with most COVID-19 vaccines, people need two doses to get the greatest possible protection. Immune response learned the first time is boosted when put into practice on the second exposure. Centers for Disease Control and Prevention define a second, “booster”, dose as another vaccine jab to build enough protection after vaccination, but then that protection decreases over time, waning immunity. HHS has developed a plan to begin offering COVID-19 booster shots to people this Autumn. GOV.UK informs about the protection from COVID-19 (vaccine effectiveness against symptomatic disease) for those who are immunosuppressed of all ages after one dose was 4%, but after two doses it was 74%, providing similar protection to those who are not in an at-risk group.

Again, vaccine effectiveness may vary by specific condition and severity of that condition. However, still one in forty people in the UK have had a first dose, yet do not seem to be getting their second. In doing so, these people are endangering their health. According to the most recent data from the Centers for Disease Control and Prevention, more than five million, nearly 8%, of Americans, who got a first shot of the Pfizer or Moderna vaccines, have missed their second doses. Rebecca Robins states the reasons vary for why people are missing their second shots. In interviews, some said they feared the side effects, which can include flu-like symptoms. Others explained they felt to be sufficiently protected with a single shot. Additionally, several vaccine providers have cancelled second-dose appointments because of running out of supply or not having the right brand in stock. 

Mix-and-match vaccination programs may also provide a solution to both supply difficulties and technical issues, such as concerns about an exceedingly rare, yet very serious, clotting risk from the AstraZeneca vaccine. Therefore, public health officials in some parts of the world, who have relied heavily on that shot, have recently issued new guidance on mixing and matching different COVID-19 vaccines. Rüdiger Groß et al wrote in their study (not yet peer-reviewed) of 26 participants, who received the first AstraZeneca shot followed by the one from Pfizer-BioNTech, that showed, according to blood tests, that individuals with mismatched vaccines had at least as strong an immune response as people who got both Pfizer shots. 

Canada’s National Advisory Committee on Immunization has recently updated its guidance to argue that people who received the AstraZeneca vaccine as their first dose can receive the same vaccine as their second dose or get a follow-up shot of Pfizer-BioNTech or even Moderna. The committee also informed that it was possible to receive the Pfizer-BioNTech and Moderna vaccines interchangeably as first and second doses. Reuters also informs that countries ranging from France to Finland and also from China to Bahrain have also expressed similar possible scenarios for combining two various vaccines. Even the Centres for Disease Control and Prevention has interim guidance informing that this is acceptable in “exceptional situations”, such as when the second dose of the same vaccine is not available. 

Recently, Quian He and colleagues published a study in mice, which focused on different combinations of four different COVID-19 vaccines, including one made from mRNA as well as one viral vector vaccine which, like the AstraZeneca and Johnson & Johnson vaccines, uses an inactivated cold virus to trigger an immune response to Covid. Their results showed that sequential immunization with adenovirus vectored vaccine followed by inactivated/recombinant subunit/mRNA vaccine administration specifically increased levels of neutralizing antibodies and promoted the modulation of antibody responses to predominantly neutralizing antibodies. Additionally, a heterologous prime-boost regimen with an adenovirus vector vaccine also improved T-cell responses. These results provide new ideas for the development and application of COVID-19 vaccines to control the pandemic.

A trial of this kind is already underway for the AstraZeneca and Pfizer-BioNTech vaccines, and the scientists behind it have released early data on side effects, including more reports of feverishness, chills, fatigue and headache among people receiving a dose that was different from their original shot compared with people who received two identical shots. Holly Yan, from CNN, suggests that this may find more reports of feverishness, chills, fatigue and headache among people receiving a dose that was different from their original shot compared with people who received two identical shots. Thus, scientists want to make sure whether this indicates that the immune system was more stimulated by the different vaccine and could develop added protection as Heidi Ledford writes in her article.

Roxanna Kahmsi, a science journalist covering COVID-19, suggested that at the start of the Covid-19 pandemic, it was uncertain whether researchers might be capable of creating a solo running vaccine. Amazingly, today’s immunization predicament arises from having multiple vaccine options to choose from. The guidance about the mix-and-match of COVID-19 jabs may seem confusing, especially when the initial vaccine guidance told people to get the same shot for both doses, but it provides an opportunity for scientists to fully understand the safety and potential benefits of using mismatched vaccines. From my point of view, the entire approach seems to be logical. It is obvious that the majority of COVID-19 vaccines are tremendously effective on their own and do not need to be paired with other versions. However, researchers should keep a close eye on the results of the mix-and-match trials to see if a huge and wide range of respondents in well-controlled studies demonstrate any signals of even better protection. 

The National Institutes of Health (NIH) has recently started a clinical trial examining the effects of different combinations of COVID-19 vaccines. New findings, from Shan Lu’s study about the Heterologous Prime-Boost Vaccination, suggested that prime boost can be done with different types of vaccines containing the same antigens. In many cases such heterologous prime-boost can be more immunogenic than homologous prime-boost. Heterologous prime boost represents a new way of immunization and will stimulate better understanding on the immunological basis of vaccines. 

The findings from the mix-and-match vaccine approach could be informative for vaccine development for other pathogens, especially viruses mutating even more rapidly than COVID-19. Experts should be studying all the current coronavirus vaccines to check how well they work against new and/or mutated variants of the virus. In a generation of multiplying vaccine technologies and raging pandemic, it can probably safely be argued that vaccines, just like people, display greater power once they work together.

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s