On March 13, the Children’s Hospital of Philadelphia Vaccine Education Center sponsored a vaccine update webinar with Paul A. Offit, MD, as the speaker and moderator. Dr. Offit discussed items in the news related to vaccines as well as decisions taken at recent Advisory Committee on Immunization Practices (ACIP) meetings in Atlanta.
First on the agenda was a discussion of pertussis vaccine, particularly as it relates to a February 7 letter to the New England Journal of Medicine in which researchers (Queenan, Cassidy, & Evangelista) called attention to new strains of Bordatella pertussis that the group had observed at St. Christopher’s Hospital in Philadelphia. Specifically, these strains were classified as pertactin-negative. Pertactin is a protein that is normally a component of B. pertussis, and it is one several antigenic proteins in acellular pertussis vaccines. The letter questioned whether the acellular vaccine was generating pressure on B. pertussis, thus leading to the emergence of these pertactin-negative strains.
The media quickly picked up the story and claimed that circulating pertussis strains were resistant to the vaccines, and positing that as the reason for the current pertussis outbreaks. Antivaccination groups seized on this and claimed that vaccines were causing resistant strains to emerge. But, as Dr. Offit noted, and the CDC says as well, the pertussis vaccine remains effective against pertactin-negative strains.
To address these claims Dr. Offit asked, Why do we have a resurgence of pertussis in the United States? Is it waning immunity to the acellular vaccine, or the appearance of pertactin-negative strains? He presented four arguments against the latter.
1. In the 12 cases covered in the NEJM letter, pertactin negative B. pertussis was found in children who were under- or unvaccinated for pertussis. He noted that if one wanted to argue that the vaccine isn’t working, you should be able to find pertactin-negative strains in children who were fully vaccinated.
2. The epidemiological evidence clearly supports the waning immunity scenario. Here he showed a graph from a Washington state pertussis outbreak in 2012 that demonstrated the clear rise in incidence of pertussis in children as they moved away from the age 4-6 period when they would have gotten a pertussis booster. These data clearly support the waning immunity hypothesis. More data, these from Klein in California, demonstrate the same principle.
3. Pertactin-negative isolates were not detected in the United States before 2009; recent data, however, show no change in vaccine effectiveness with the presence of these new strains in the United States.
4. Finally, pertussis vaccines don’t just contain pertactin. While there are single antigen vaccines (such as those for HPV and HBV), all pertussis vaccines contain several antigens. All have pertussis toxin, deactivated to form toxoid. All pertussis vaccines also contain several of the following antigens: filamentous hemagglutinin, pertactin, and fimbriae types 2 and 3. If a virus targeted by a single-antigen vaccine were to mutate in a way related to that antigen, this could very well be problematic. But with pertussis vaccines all containing a variety of antigens, including what is probably the most important one in the toxin, this problem doesn’t really apply. In the case of pertussis and the pertactin-negative strains, the term escape mutant doesn’t apply (an escape mutant being a pathogen that has evolved resistance to a drug or vaccine).
5. There is no evidence from other countries that the new isolates are leading to more disease.
In short, Offit said that the pertactin-negative isolates are a microbiological curiosity in search of explanation. Additionally, he compared the NEJM pertactin-negative pertussis letter to Andrew Wakefield’s influential but troubling Lancet paper: Both have raised hypotheses but supplied no evidence in support of the conjecture. Referring to Carl Sagan’s famous maxim, he noted that extraordinary claims should be backed by extraordinary evidence. Scientists should have been more critical about Queenan’s suggestion because of the lack of evidence to support it. And NEJM should have requested more data to back up the letter. The media, he says, can’t distinguish between a hypothesis and a study, and scientists, publishers, and laypeople need to be sensitive to this.
New Influenza Vaccines for 2013/14
First, Dr. Offit reported that the influenza strains chosen for the 2012-13 vaccines were good matches for circulating strains, with the notable problem of the influenza B strain. Of the influenza B samples typed by CDC, 71% matched the Yamagata strain in the vaccine, whereas 29% were from a different lineage. Next year, we may see this problem addressed in the new quadrivalent vaccines that will include two influenza B components.
IIV4 (Fluarix, GSK) will be used for people age 3 and older at the provider’s discretion (quantities may be limited). The live attenuated influenza vaccine (LAIV, FluMist, MedImmune) will be quadrivalent and available for those age 2-49, with the exception of pregnant women and others with contraindications to the live vaccine.
He noted that the acronym TIV, for trivalent inactivated vaccine, will disappear and we will use IIV4 or IIV3 for inactivated influenza vaccines with four or three strains.
Notably, one influenza vaccine will not use virus grown up in eggs; the IIV3 vaccine will use cell-cultured virus, grown on Vero cells (originally from African green monkeys). FluCelVax IIV3 (Novartis) will be recommended for people 18 years and older. Offit noted that he suspects we will be moving away from egg use in influenza vaccine production, as eggs are not particularly convenient to use.
RIV3 (Flublok from Protein Science) will be recommended; this new vaccine is a recombinant hemagglutinin (HA) vaccine recommended for those age 18 to 49. For this vaccine, genes that codes for hemagglutinin are put into a baculovirus, which then infects insect cells. HA is produced by the cells, harvested, purified, and used in the vaccine. This vaccine includes more HA per dose than other vaccines — 45 micrograms versus 15 micrograms. This recombinant vaccine has been shown to be as effective as inactivated vaccine, which is interesting, Offit says, because we have always assumed that HA and neuraminidase (another influenza virus surface protein) are equally important in stimulating immunity. Observing the effectiveness of RIV may help us shed light on whether our assumption is true.
Combination Hib-MenCY Vaccine
The new HibMenCY vaccine (MenHibRix from GSK) should be available by summer. Though Hib vaccine is routinely recommended for infants, the meningitis component means that this particular vaccine will be recommended only for infants at risk of meningitis disease, such as those with sickle cell disease, asplenia, and complement component deficiencies, and infants at risk in a specific outbreak of disease cause by N. meningitidis group C or Y. The recommended schedule is vaccination at 2, 4, 6, and 12-15 months of age.
Offit walked participants through some of the data that led to the decision to recommend the vaccine for high-risk children and not for universal use. Among these data, he noted that 50-60% of meningococcal disease in children under age 5 is caused by serogroup B, which this vaccine doesn’t include. If the vaccine were given universally, at most 25% of cases of meningococcal disease in infants would be prevented, amounting to 44 cases and 2 deaths per year.
Dr. Offit discussed pneumococcal conjugate vaccine use in vulnerable in children at this point, but I wasn’t able to listen in on the rest of the information.
Many thanks to CHOP’s Vaccine Education Center and Dr. Offit for presenting this informative talk.
Sources and More Information
CDC. MMWR. Infant meningococcal vaccination: Advisory Committee on Immunization Practices recommendations and rational. January 25, 2013 / 62(03);52-54. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6203a3.htm
CDC. MMWR. Pertussis epidemic: waning immunity. July 20, 2012 / 61(28);517-522. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6128a1.htm
CDC’s Statement on Pertactin-Negative Pertussis Strains
Klein N., et al. Waning protection after fifth dose of acellular pertussis vaccine in children. NEJM 367 (2012): 1012-1019.