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Herd Immunity and this Pandemic

2 June 2022 by Gertrud U. Rey

by Gertrud U. Rey

Photo courtesy of Andrea Lightfoot photography

Herd immunity occurs when a large enough percentage of the population has acquired either natural or vaccine-induced immunity against an infectious disease, thereby indirectly protecting a minority of non-immune individuals who are dispersed throughout the population. During this pandemic, many prominent scientists have stated that it is impossible to achieve herd immunity in the context of COVID-19, leading some to conclude that a mass SARS-CoV-2 vaccination campaign would be pointless. However, this thinking is flawed, and I want to explain why.

Traditionally, herd immunity is thought to create a barrier for the transmission of infectious agents, resulting not only in prevention of disease, but also prevention of infection. This understanding was based on previous observations that vaccination against poliovirus, measles virus, and other pathogens led to drastic reductions in the incidence of disease burden. It is reasonable to assume that if there is no disease, there is probably also no virus; and hence no viral infection or transmission of virus. However, past vaccination campaigns were not followed up with regular testing programs, so we actually have no way of knowing whether vaccination prevented infection and transmission! Considering that the vast majority of poliovirus infections are asymptomatic, it is possible that some polio virus infections and transmission occurred even after vaccination, despite the fact that those infections did not lead to disease.

The widespread testing measures adopted during the present pandemic have revealed the approximate frequency of asymptomatic SARS-CoV-2 infections, giving us a clearer understanding of the difference and dynamics between disease and infection. The type of immunity that prevents both disease and infection is called sterilizing immunity, and it is mostly thought to be induced by neutralizing antibodies, which inactivate infectious agents before they have a chance to infect a cell, thereby directly neutralizing the biological effect of the agent. However, any immune activity that prevents replication of a pathogen directly or indirectly necessarily induces sterilizing immunity, including the activity of non-neutralizing antibodies, whose binding can trigger other immune functions that can also prevent infection and replication.

Do SARS-CoV-2 vaccines induce sterilizing immunity? The answer to this question is complicated. There are many studies showing that most people have high levels of antibodies in the months following vaccination, and this large proportion of circulating antibodies could likely sequester an incoming virus before it has a chance to enter cells, infect them, and replicate. In this sense, the SARS-CoV-2 vaccines do induce sterilizing immunity, but only within a certain time period after vaccination. As antibody levels contract over time (a normal process), they leave behind a baseline population of memory B cells that can quickly expand and mass-produce new antibodies upon a subsequent encounter with SARS-CoV-2. Likewise, memory T cells can quickly react to incoming virus and virus-triggered signals, and destroy infected cells. Therefore, it is likely that when circulating SARS-CoV-2-specific antibody levels decline months and years after vaccination, the collective activity of memory immune cells will protect one from disease, but probably not infection, meaning that the SARS-CoV-2 vaccines no longer induce sterilizing immunity at that time. In other words, vaccinated people could briefly replicate and transmit low levels of virus, at least until memory immune responses kick in, which then prevent illness and additional viral replication and spread.

The emergence of new variants that are not as well recognized by existing vaccine-induced antibodies may also allow for some increased viral transmission, thus slowing down the establishment of immunity in the population. However, immune responses are not binary, and even a low level immune response that doesn’t protect against infection and spread but prevents serious disease can play a critical role in slowing down the pandemic. Vaccination has historically been very effective at suppressing community outbreaks, despite the fact that most vaccines do not induce sterilizing immunity.

Vaccination or natural immunity do not have to prevent all infections, and immunity does not have to last a lifetime for a pandemic to end. Pediatrician and vaccinologist Paul Offit defines herd immunity as the point where the serious disease burden is reduced sufficiently so as to no longer overwhelm the healthcare system. It’s becoming pretty clear that the pandemic is slowing down in the US, especially in the context of severe disease, hospitalization, and death; and that this is likely due to increased SARS-CoV-2 immunity among US residents. It is therefore likely that reduced illness and a shortened period of transmission from immune individuals will also reduce the overall rate of community infection and transmission. And in the end, it doesn’t matter whether we call it herd immunity, community immunity or some other name; the pandemic will end because a majority of the population is no longer susceptible to severe COVID-19.

[Please check out my video Catch This Episode 29 for an explanation of sterilizing immunity.]

Filed Under: Basic virology, Gertrud Rey Tagged With: antibody, disease, herd immunity, infection, neutralizing antibody, pandemic, sterilizing immunity, transmission, vaccine

TWiV 896: Memory B cells, the way we were

1 May 2022 by Vincent Racaniello

TWiV explains a study of how climate change is predicted to increase cross-species viral transmission risk, and increased memory B cell potency and breadth after a SARS-CoV-2 mRNA vaccine boost.

Hosts: Vincent Racaniello, Dickson Despommier, and Amy Rosenfeld

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Filed Under: This Week in Virology Tagged With: antibody, climate change, COVID-19, memory B cell, pandemic, SARS-CoV-2, variant of concern, viral, virology, virus, viruses, zoonosis

TWiV 890: Looking into a booster crystal ball

18 April 2022 by Vincent Racaniello

This episode of TWiV is focused on COVID-19 vaccines and antibodies: who should get boosters, whether a variant matched mRNA vaccine is superior to a historical vaccine, and how the interval between vaccination and infection influences the quality of the antibody response.

Hosts: Vincent Racaniello, Dickson Despommier, Rich Condit, and Brianne Barker

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Filed Under: This Week in Virology Tagged With: antibody, coronavirus, COVID-19, pandemic, SARS-CoV-2, T cells, vaccine, viral, virology, virus, viruses

An Intranasal SARS-CoV-2 Vaccine Candidate

3 March 2022 by Gertrud U. Rey

by Gertrud U. Rey

There are numerous advantages to administering a vaccine by the intranasal route: it is simple, painless, and does not require special training. The last time I discussed SARS-CoV-2 vaccine candidates for potential intranasal delivery, the idea was still fairly new. However, multiple new studies are now showing that delivery of a SARS-CoV-2 vaccine into the nose induces immune responses that are superior to those observed after delivery into the muscle.

The authors of one such recent study compared the efficacy of a single dose of two different adenovirus-based SARS-CoV-2 vaccine candidates after intramuscular injection to that after administration by the intranasal route. Both vaccines encoded three viral antigens: 1) the full-length S1 domain of the SARS-CoV-2 spike protein, which contains the region that binds to the host cell receptor ACE2; 2) the full-length nucleocapsid protein, which is essential for binding and packaging the viral genome; and 3) a truncated version of the RNA-dependent RNA polymerase (RdRp), the enzyme responsible for copying the viral genome during infection. The three antigens were inserted into either one of two adenovirus vectors: a virus of human origin to produce “Tri:HuAd” or a virus of chimpanzee origin to produce “Tri:ChAd.” Most currently approved SARS-CoV-2 vaccines only encode the full-length spike protein, but not nucleocapsid or RdRp. These two additional genes were likely included in the present study because nucleocapsid is the most abundant viral protein in infected cells, and because RdRp is well conserved among coronaviruses, thus potentially leading to broader immune responses.

To assess the antibody responses induced by either vaccine candidate, the authors immunized mice with a single dose of Tri:HuAd or Tri:ChAd into the nose or into the muscle and collected serum and lung wash samples 2, 4 and 8 weeks later. The collected samples were then tested for the presence of IgG antibodies, which provide the majority of antibody-based immunity. Analysis of sera collected at 4 weeks revealed that mice immunized intranasally with either vaccine had significantly higher levels of spike protein-specific IgG than did mice that were immunized intramuscularly, and these high levels were sustained through 8 weeks post-vaccination. However, only lung wash samples from mice immunized with either vaccine intranasally contained detectable levels of spike protein-specific IgG at the 4 week time point, suggesting that only intranasal immunization led to IgG production in the airways. Interestingly, the airways of Tri:ChAd recipients harbored almost twice as much spike-specific IgG as those of Tri:HuAd recipients, a difference that was not observed in the serum, suggesting that the vector of chimpanzee origin induced better local immune responses when administered via the nose. Additionally, only the lung wash samples from intranasal Tri:ChAd recipients contained any observable anti-spike IgA antibodies, which are prevalent in mucosal surfaces and represent a first line of defense against invasion by inhaled and ingested pathogens. These results suggested that both vaccines, but Tri:ChAd in particular, induced better immune responses when they were delivered intranasally.

Lung wash samples were also analyzed for vaccine antigen-specific T cells by detecting characteristic cell surface proteins on these T cells, and for specific cytokines produced by the T cells in response to their exposure to peptides encoding each of the three vaccine-encoded antigens: S1, nucleocapsid, or RdRp. This analysis revealed that when the vaccine was injected into the muscle, neither Tri:HuAd nor Tri:ChAd induced detectable airway antigen-specific cytotoxic T cells, which are capable of killing virus-infected cells. In contrast, both vaccines induced significant numbers of cytotoxic T cells in the airways when they were delivered intranasally. Although the detected T cells were specific for all three antigens, S1-specific cells were more abundant, and they were also multifunctional in that they produced more than one cytokine characteristic of cytotoxicity. However, in the context of intranasal vaccination, the Tri:ChAd vaccine induced higher total numbers of cytotoxic T cells than the Tri:HuAd vaccine, suggesting that a single dose of Tri:ChAd delivered intranasally is highly effective at inducing vaccine antigen-specific cytotoxic T cells in the respiratory tract.   

Interactions between lung macrophage cells and SARS-CoV-2 can increase the expression of the host-derived peptide MHCII on macrophage surfaces, allowing these cells to become a critical component of “trained innate immunity.” This altered innate immunity results from a functional modification of innate immune cells that leads to an antibody-independent temporary immune memory that is characterized by an accelerated response to a second challenge with the same pathogen. Neither Tri:HuAd nor Tri:ChAd induced detectable MHCII expression on macrophages in the lungs of mice when delivered intramuscularly. In contrast, both vaccines induced increased levels of MHCII-expressing lung macrophages 8 weeks after immunization when delivered intranasally, with a higher number of these cells in the lungs of Tri:ChAd recipients, suggesting that intranasal immunization with Tri:ChAd induces strong trained innate immunity.

The authors next tested the ability of the vaccines to protect mice from SARS-CoV-2 infection by intentionally infecting immunized mice with a lethal dose of SARS-CoV-2 at 4 weeks after immunization, and monitoring them for clinical signs of illness in terms of weight loss. Unvaccinated control animals and 80% of animals immunized intramuscularly with either vaccine were not protected from infection or disease and died by 5 days post-infection. In contrast, animals immunized with Tri:HuAd showed a temporary and slight weight loss, but rebounded over the course of two weeks, while animals immunized with Tri:ChAd did not lose weight at all for the duration of the two-week time course. This result correlated with reduced viral load and reduced lung pathology at 14 days post-infection in mice immunized intranasally compared to unvaccinated controls and intramuscular vaccine recipients, with Tri:ChAd recipients exhibiting the most reduced viral burden and lung pathology.   

Having determined that intranasal administration of Tri:ChAd induced the best immune responses, all subsequent experiments were carried out using this vaccination strategy. To assess the individual contributions of B cells and T cells in the vaccine-induced immune response, the authors immunized two groups of mice: one group that was genetically deficient in B cells and a second group of genetically wild type mice that were depleted of T cells by receiving injections of antibodies against T cell-characteristic cell surface molecules. Because T cells are needed for B cell stimulation and production of antibodies, the antibody injections were done on day 25 after immunization to ensure that vaccine-induced B cell functions and antibody production remained intact in the T cell-depleted mice. At 28 days after vaccination, both groups of animals were infected with SARS-CoV-2 and monitored for weight loss. Unvaccinated mice that were either B cell-deficient or T cell-depleted and control unvaccinated mice with normal B and T cell functions were subject to drastic weight loss. In stark contrast, neither B cell-deficient nor T cell-depleted mice that had been intranasally immunized with Tri:ChAd showed any weight loss throughout the 2-week experimental time course, despite the fact that both groups of animals had significantly elevated viral burden in the lung. This result suggested that Tri:ChAd was immunogenic enough to compensate for the lack of B or T cells and protect the mice from clinical disease after SARS-CoV-2 infection.

The authors next wanted to analyze the role of trained innate immunity in the absence of B and T cell immunity, so they immunized two groups of mice. The first group consisted of B cell-deficient animals that were depleted of T cells shortly after vaccination. Because T cells induce vaccine-mediated trained innate immunity early after vaccination, this strategy produced mice that lacked B cells, T cells, and trained innate immunity. The second group consisted of B cell-deficient animals that were depleted of T cells starting at day 25 post-vaccination to allow for induction of trained innate immunity and thus produce mice that lacked B cells and T cells, but possessed intact trained innate immunity. At 28 days after vaccination, both groups of animals were infected with SARS-CoV-2 and monitored for weight loss and lung pathology. Unvaccinated control mice with functional B cells, T cells, and trained innate immunity and unvaccinated mice lacking B cells, T cells, and trained innate immunity showed severe weight loss and severe lung pathology. In contrast, vaccinated mice lacking B cells and T cells but possessing trained innate immunity appeared healthy with no weight loss and no pathology in the lungs, suggesting that the immune protection observed in animals lacking B cells, T cells, or both, was likely mediated by trained innate immunity.

The study demonstrated similar results after infection of mice with alpha and beta variants of SARS-CoV-2; however, it would be interesting to see if these vaccines have similar efficacy against the later variants, including delta and omicron. Although these results are promising, it is important to remember that mice can be poor predictors of human disease outcomes. Nevertheless, I look forward to seeing the results of the clinical trial that is currently underway to compare the relative efficacies of Tri:HuAd and Tri:ChAd following intranasal delivery in humans.

[For a more detailed discussion of this paper, please check out TWiV 867.]

Filed Under: Basic virology, Gertrud Rey Tagged With: antibody, b cells, cytotoxic T cells, IgA, IgG, intramuscular, intranasal vaccine, macrophages, MHCII, nucleocapsid, RdRp, SARS-CoV-2, spike protein, T cells, trained innate immunity, vaccine

TWiV 866: EV antibodies rEVolutionize our thinking

15 February 2022 by Vincent Racaniello

Amy returns to TWiV to discuss her work on the identification of cross-reactive antibody responses among diverse enteroviruses, and the implications for our understanding of viral pathogenesis and seroprevalence studies.

Hosts: Vincent Racaniello, Dickson Despommier, Rich Condit Brianne Barker, and Amy Rosenfeld

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Filed Under: This Week in Virology Tagged With: antibody, cross-reactive antibody, enterovirus, epitope, neutralization, plaque assay, poliovirus, serology

TWiV 839: The long and the short of it: get vaccinated

9 December 2021 by Vincent Racaniello

TWiV reviews the impact of vaccination on SARS-CoV-2, the latest information on Omicron, West Nile virus transmission by organ transplantation, and why a 16 week interval between doses of BNT162b2 vaccine is better than a shorter interval.

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Filed Under: This Week in Virology Tagged With: antibody, coronavirus, COVID-19, pandemic, SARS-CoV-2, vaccine, viral, virology, virus, viruses

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