Numerous studies have shown that vaccines mixed with other drugs can trigger powerful immune responses. However, scientists still need to know if this is true and if there are any side effects.Combining two COVID-19 vaccines may produce an immune response similar to that of one vaccine. Credit: Canadian Press/ShutterstockCombining COVID-19 vaccines can be a great way to provide protection when there are safety concerns or unpredicted supplies. Although most vaccines against SARS are required to be administered in two doses (most vaccines against SARS CoV-2 require that they be given in this amount), multiple studies have shown that the OxfordAstraZeneca jab combined with the PfizerBioNTech vaccine can trigger an immune response comparable to, or stronger than, two doses.A UK research group announced Monday 1 that the combination can sometimes outperform two shots of the vaccine. Similar results are emerging from German studies2.According to Leif Erik Sander, an immunologist at Charit University Hospital in Berlin, people can feel more comfortable with mix-and-match.Researchers are confident that other COVID-19 vaccines that have not been combined may work, based on the results. However, at least 16 vaccines are approved for use in one or several countries. Mix-and-match studies have not been extensive so further research and monitoring of side effects is essential.Immune system boosterMix-and-match research was initiated by concerns about the safety of the vaccine, which was developed at the University of Oxford and AstraZeneca, a pharmaceutical company based in Cambridge. There have been rare cases of blood-clotting disorder known as thrombosis and thrombocytopenia. Some European countries stopped using the jab in certain groups. Many people were only partially vaccinated unless they switched to another brand.Researchers at the Carlos III Health Institute, Madrid, announced the results4 of the CombiVacS study in May. After receiving the OxfordAstraZeneca vaccine for 812 weeks, the study showed a strong immune response.Although there was no direct comparison between people who received two doses, the researchers found that the combination produced 4x more SARS-2-specific immune cells and 37x more SARS-2-specific antibodies in laboratory tests than those who received just one dose.More results confirming the same effect were available by June's end.Sander and his coworkers examined 340 health-care workers who had either received two doses PfizerBioNTech or one shot of OxfordAstraZeneca followed by PfizerBioNTech. Both vaccines caused an immune response, which included T cells and neutralizing antibodies.Researchers at Saarland University, Homburg, Germany found that the mix regimen was more effective at inducing immune responses than two OxfordAstraZeneca shots. It also performed as well as, or better than, two shots of PfizerBioNTech.On 25 June, the Com-COV team posted an online pre-print showing that the vaccines were administered in the same order as they were given.The trials have not been large enough to determine the effectiveness of different vaccine combinations in preventing COVID-19. Martina Sester, an immunologist, said that it is difficult to determine the level of protection as long as there are no follow-up studies or efficacy calculations.The work is still limited in that it's not possible to compare the results of different studies. Sester says that large-scale efficacy trials are becoming more challenging. Because of the fact that infection rates are decreasing, it is more difficult to conduct large-scale efficacy studies. To detect differences in disease and infection rates, the study must have more participants. She adds that trials that compare mix-and-match vaccines to a placebo would be unjustifiable.One reason is why research efforts are underway to establish a correlate for protection, a level of immune response that confers immunity against disease and infection. Sander says that this is a critical matter.A nuanced imageHowever, a more nuanced picture of the types and magnitude of immune responses that vaccines mix creates is emerging. These differences could be used to your advantage and provide you with the most protection.To carry SARS-CoV-2 genetic material into cells, the OxfordAstraZeneca vaccine uses an innocuous virus called an Adenovirus. Sander says vaccines using this technology have a strong track record in inducing strong T cell responses. Vaccines that use messenger RNA such as Pfizers have been exceptionally successful in inducing high levels antibodies.Combining vaccines can help alleviate supply problems in remote areas, such as India's rural areas. Credit: Dibyangshu Sarkar/AFP/GettySester believes that high levels after the second shot of anti-bodies are a sign that the combination approach is working. Because they prevent viral infection, neutralizing antibodies can be a good indicator of efficacy. However, T cells, particularly killer T cells carrying a protein known as CD8, can protect against severe diseases by killing infected cells.The Com-COV study showed that people who received two doses of PfizerBioNTech had the highest antibody responses. However, this response was nearly as high when they were given OxfordAstraZeneca and PfizerBioNTech. This combination had a T-cell response that was more than twice as strong as the PfizerBioNTech doses.Sander explained that a combination of an mRNA vaccine with an adenovirus-based vaccine could provide the best of both worlds.Sester and her colleagues discovered subtle differences in T cell populations depending on vaccines. These subtle differences could be used to create personalized strategies, says Sester. For people who have had an organ transplant and are on medication to suppress their immune system, combinations that stimulate good T-cell response might be more beneficial. This is because their bodies won't produce enough antibodies to make them susceptible to developing antibodies. She says there are many strategies to exploit this knowledge.There are still safety concernsThere have been no severe side effects reported in mix-and match trials. According to preliminary data, the Com-COV study found that mixing vaccines caused more side effects than administering two doses of one vaccine. This was not the case with the Charit and Saarland research or CombiVacS where side effects were no more severe than when you received two doses of the same vaccine.Sester believes this is due to the time between doses. Participants in Com-COV received their second shot four to five weeks after their initial dose. German study participants had at most nine weeks. Some Com-COV participants received doses at a longer time; their data will be available in July.Sander says there are still safety concerns. He says that you are combining two vaccines with different profiles, each of which may have their own adverse effects and events. This could increase the potential for problems.Only a handful of people have been enrolled in the studies. They are not able to detect rare conditions such as clotting disorders, which can occur in approximately one in 50,000 people following the first OxfordAstraZeneca vaccination and less than 1 million after the second. Johnson & Johnson, a New Jersey-based pharmaceutical company, has been linked to the adenovirus vaccine.Matthew Snape, an Oxford researcher and vaccine expert, stated that you don't pick up your one in 1,000 side effects, let alone your one in 50,000 side effects, even in small studies. Snape spoke at a press conference held on 28 June.Seven COVID-19 vaccines were approved in the Philippines. A trial will be conducted in China to see if it can be used in conjunction with other CoronaVac vaccines. Credit: Ted Aljibe/AFP/GettyWhat is the new norm?Researchers recommend that everyone stick with the two doses of one vaccine, despite the possibility of rare side effects. Snape says that it is better to choose vaccines where safety and effectiveness are known.However, as new SARS-CoV-2 variants emerge, mix-and-match trial results could give policymakers the information they need to switch to better protective combinations. Fiona Russell, a vaccine researcher at Murdoch Childrens Research Institute, Melbourne, Australia, said that it is important to have this data ready.To prevent roll-outs from stalling due to supply problems, mix-and-match vaccines can also be used. Russell says that if there is a shortage of a particular vaccine in the world, it may be possible to continue the vaccination program.Snape says that if there is an option to get a mixed schedule with or without a second dose, Snape recommends going for the mixed schedule.Com-COV has begun to test other vaccines on people who have already received their first Oxford-AstraZeneca and PfizerBioNTech shots. The Novavax, a Maryland-based pharmaceutical company, has yet to approve a protein-based vaccine. Another combination uses the Moderna mRNA vaccine in Cambridge, Massachusetts which has been approved for multiple countries.A study that combines the inactivated virus vaccine CoronaVac from Beijing with six vaccines approved in the Philippines will be conducted until November 2022. AstraZeneca will also be testing combinations of the OxfordAstraZeneca jab with Gamaleyas Sputnik V shot, which is adenovirus-based.
