This article is part of Harvard Medical School continuous coverage of COVID-19.
As the omicron variant of SARS-CoV-2 continues to split into subvariants, questions proliferate about how to advance vaccine strategies for different populations, the effects of repeated boosters, and ways to improve vaccines and long-term vaccination.
Scientists from Harvard Medical School, led Massachusetts Consortium on Pathogen Readiness, or MassCPR, discussed these and other topics in COVID-19 research and public health. Experts included:
- Galit Alter, HMS Professor of Medicine at Massachusetts General Hospital; principal investigator at the Ragon Institute of MGH, MIT and Harvard
- Jacob LemieuxHMS instructor in medicine and infectious disease specialist at Mass General; co-lead of the viral variants program for MassCPR
- Levy offerHMS Professor of Pediatrics and Director of the Precision Vaccines Program at Boston Children’s Hospital
- Jeremy Luban, professor of molecular medicine, biochemistry and molecular pharmacology at UMass Chan Medical School; co-lead of the viral variants program for MassCPR
Harvard Medicine News: How do you understand the reports that each new variant seems to be more transmissible and spreads faster than the previous one?
Luban: Calculating these numbers is not easy. Actual observations are affected by so many different issues. Overall, I feel like we are approaching the same degree of contagiousness as measles.
The best : At the start of the pandemic, we were talking about R0— the number of other people a person with SARS-CoV-2 will infect. Now R0 is less significant because it relates to the number of secondary infections in an immunologically naive population, whereas we have a highly immune population. Now, when a report says one variant grows 25% faster than another, that doesn’t necessarily mean the variant is inherently 25% more transmissible; this means that it spreads faster within a certain population or in a certain area, which can be due to many reasons.
At this point, it’s like whichever is faster, a Ferrari or a Lamborghini. They are fast cars. These are highly infectious viruses that will seize every opportunity to spread and cause epidemics. We are seeing this in South Africa right now, in the United States and around the world, where case rates are rising despite a substantial degree of immunity.
HMNews: What variants are you monitoring at the moment?
The best : New variants are circulating in many places and it is unclear what they all mean. We have one in the Northeastern United States, BA.2.12.1, and in South Africa there are newer variants, BA.4 and BA.5. We don’t know if one is “bad”, better or worse than another, but I would say the data from South Africa is alarming. This suggests that there will be a fifth wave in South Africa, hopefully only in numbers and not in morbidity and mortality. BA.4 and BA.5 have arrived in the US We will see what the impact is here. It has a flavor of “here we go again”.
HMNews: What is the current understanding of infection-induced immunity versus vaccine and the likelihood that a person will become infected or re-infected with SARS-CoV-2 despite some level of protection?
To modify: We see that hybrid immunity – a combination of getting vaccinated and recovering from natural infection – is the most robust correlate for protection against serious illness and death from COVID-19. This is stronger than natural immunity or immunity acquired by the vaccine alone. New studies show that natural infection extends protection in several ways. There seems to be something special about the immune system encountering the whole virus. Whether related to T-cell or B-cell responses are still unclear. The tissue-specific innate immune response in the lungs appears to be a key component. We need to understand immunology to determine how and when to boost most effectively and which combination of vaccines provides the highest level of long-lasting protection against this virus.
The best : Undoubtedly, reinfection is now a common feature of the COVID-19 syndrome. We don’t know how to calculate the probability based on a person’s immune status, such as a person who received three doses of vaccine and was infected with the beta variant versus another person who received one dose of vaccine and was infected with both delta and omicron. As Galit said, hybrid immunity appears to confer the strongest immunity, and we believe that the likelihood of reinfection is related to the strength of immunity. We will learn more in the months to come. There is so much to unpack.
HMNews: What is the latest research on COVID-19 vaccines and children?
To modify: We still have a problem with the youngest children in our global population having low vaccination coverage, and yet they are among the groups that have probably seen the most SARS-CoV-2 infections. Throughout the Mass General Brigham system, we ask if children are able to respond to vaccines, if they develop better responses after vaccination than after infection. We want to understand the value of vaccination because there is so much hesitation when it comes to immunizing children.
In recent work, we followed children aged 5-11 and 12-19 after their first and second doses of mRNA vaccine. We found that the 5 to 11 year old age group responds to vaccines with the same levels of antibodies as adults and probably even more than what we see in adolescents. More importantly, the levels achieved by both groups of children with vaccination are far higher than the levels they achieve with natural infection. There is no doubt that vaccines do a better job of conferring long-term protection and preventing repeat infections than herd immunity.
We also find that children aged 5 to 11 produce much higher levels of specific types of functional antibodies compared to adolescents and adults. They exploit their immune system in a different way.
HMNews: What are some of the pros and cons of continuing to recommend SARS-CoV-2 vaccine boosters?
Sample: In a quick review of eight studies in the United States, we found evidence of reduced vaccine effectiveness in adults aged 65 and over. This decline was evident in protection against infection and disease. This suggests that the booster’s FDA recommendation was correct.
To modify: On the other hand, in the field of HIV, we have learned that repeated reminders are not always a good thing. Comparison of HIV vaccine clinical trial results suggests that repeated boosters, in one case of up to six doses, may increase your antibody levels but shift your overall antibody profile toward less common antibody types. antivirals. So the first doses of vaccine can boost the production of IgG1, our workhorse antibodies, and IgG3, which are potent antivirals, but then a fifth or sixth dose can push more IgG2, which are less efficient.
The data we have so far for COVID-19 vaccines, which go up to a fourth dose, indicate that certain populations – especially people with short intervals between doses – are starting to develop different antibody profiles. . It’s a little worrying, but it’s the beginning. We need to look deep to see what’s going on and then think clearly about how and when we boost so we don’t retool our immune response to be less effective against SARS-CoV-2.
The good news is that “mix and match” vaccines do not appear to generate the least effective antibody profiles. Even mixing and matching mRNA vaccines can be advantageous. We need to study this phenomenon further in order to obtain maximum benefit.
Sample: It is true that the need for many long-term doses is impractical at the population level. Scientists are asking, can we come up with a single dose, can we develop a universal coronavirus vaccine. Researchers in our precision vaccine program and around the world are studying other vaccine platforms, such as nanoparticles and protein-based vaccinesand to adjuvants, which are molecules capable of stimulating the immune response of a vaccine, broadening this response, reducing the number of doses required and increasing the durability of protection, particularly in vulnerable populations with immunity distinct. This approach has proven useful in MassCPR-supported work to develop a protein-based, adjuvanted SARS-CoV-2 vaccine which was highly effective in older animals and paved the way for a recently licensed vaccine in India called Corbevax.
To modify: Yes, adjuvants are an extremely important tool for enhancing vaccine responses, especially in older populations with aging immune systems. We can draw on decades of flu vaccine research. Instead of pumping more doses into the population, we are learning how to make the aging immune system respond more to a single dose. The analogy my mother uses is that you can’t just speak louder to someone who doesn’t know your language; you have to translate the message so that the listener – in this case, the immune system – understands it better. The adjuvants could be the translation tools.
HMNews: What gives you hope these days?
Luban: The entire field of vaccines is undergoing tremendous change. The opportunities presented to us by being forced to fight SARS-COV-2 are unprecedented. We have had very few opportunities in the past to disassemble vaccines to understand how they work. We are gaining new insights into what confers broad and long-lasting immune responses and which cells or molecules best indicate protection against a virus. It is exciting to study basic principles that we have wondered about for many years. It can change the way we think and talk with the public about what’s important.
HMNews: What keeps you up at night?
The best : The need for continued investment in this area by Congress and the American people. These things do not fall from the sky. We must support science and technology. Funding allocations for ongoing COVID investments have not been passed by Congress, but we are considering a fifth wave. People are tired, but we are going to fight coronavirus for the foreseeable future – probably forever – and we should take this opportunity to define a long-term strategy to invest in research for vaccines for this pathogen and for others in order that we can learn how to build better vaccines, deploy them and save lives. I am optimistic that given the resources, scientists, industry, public health experts and policy makers working together will be able to do this.